Combination therapy of hsp90 inhibitors with platinum-containing agents

ABSTRACT

A pharmaceutical combination comprising a platinum-containing anticancer agent, and an Hsp90 inhibitor according to the following formulae (I) &amp; (Ia), a tautomer, or a pharmaceutically acceptable salt thereof, wherein the variables structural formulae are defined herein. Also provided is a method of treating a proliferative disorder such as cancer in a subject in need thereof, using the pharmaceutical combination described herein.

CROSS-REFERENCE TO RELATED PATENTS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Nos. 61/554,706, filed on Nov. 2, 2011. The contentsof the above application are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

Although tremendous advances have been made in elucidating the genomicabnormalities that cause malignant cancer cells, currently availablechemotherapy remains unsatisfactory, and the prognosis for the majorityof patients diagnosed with cancer remains dismal. Most chemotherapeuticagents act on a specific molecular target thought to be involved in thedevelopment of the malignant phenotype. However, a complex network ofsignaling pathways regulate cell proliferation and the majority ofmalignant cancers are facilitated by multiple genetic abnormalities inthese pathways. Therefore, it is less likely that a therapeutic agentthat acts on one molecular target will be fully effective in curing apatient who has cancer.

Heat shock proteins (HSPs) are a class of chaperone proteins that areup-regulated in response to elevated temperature and other environmentalstresses, such as ultraviolet light, nutrient deprivation and oxygendeprivation. HSPs act as chaperones to other cellular proteins (calledclient proteins), facilitate their proper folding and repair and aid inthe refolding of mis-folded client proteins. There are several knownfamilies of HSPs, each having its own set of client proteins. The Hsp90family is one of the most abundant HSP families, accounting for about1-2% of proteins in a cell that is not under stress and increasing toabout 4-6% in a cell under stress. Inhibition of Hsp90 results in thedegradation of its client proteins via the ubiquitin proteasome pathway.Unlike other chaperone proteins, the client proteins of Hsp90 are mostlyprotein kinases or transcription factors involved in signaltransduction, and a number of its client proteins have been shown to beinvolved in the progression of cancer.

SUMMARY OF THE INVENTION

It has been found that certain triazolone Hsp90 inhibitor andplatinum-containing anti-cancer agent combinations are surprisinglyeffective at treating subjects with certain cancers without furtherincreasing the side effects profile of the individual agents. Theparticular combination therapies disclosed herein demonstrate surprisingbiological activity by demonstrating significant anticancer effects.

In an embodiment, the invention provides a method of utilizing Hsp90inhibitors according to formulae (I) or (Ia), or a compound in Tables 1or 2 for the treatment of proliferative disorders such as cancer, incombination with a platinum-containing anti-cancer agent. In anembodiment, a method of treating a subject with cancer includesadministering to the subject an Hsp90 inhibitor according to formulae(I) or (Ia), or a compound in Tables 1 or 2, and a platinum-containinganti-cancer agent. In an embodiment, the administration of the Hsp90inhibitor and the platinum-containing agent are done concurrently. Inanother embodiment, the administration of the Hsp90 inhibitor and theplatinum-containing agent are done sequentially. In another embodiment,the administration of the Hsp90 inhibitor and the platinum-containingagent are dosed independently. In any one of these embodiments, theplatinum-containing agent may be cisplatin, carboplatin, oxaliplatin, ortheir analogues. In any one of these embodiments, the Hsp90 inhibitormay be a compound represented in Tables 1 or 2. In any one of theseembodiments, the platinum-containing agent may be cisplatin.

In some embodiments, the cancer may have mutations or translocations inthe EGFR, K-Ras, c-Metc-Met, c-Kit, HER2, B-Raf, PI3K and/or ALKproteins. In some embodiments, the cancer may express wild-type EGFR andK-Ras. In some embodiments, the cancer may express mutated EGFR andwild-type K-Ras. In some embodiments, the cancer may express wild-typeEGFR and mutated K-Ras protein. In some embodiments, the cancer may beALK positive (“ALK+”.) In some embodiments, the cancer may have anEML4-ALK translocation. In some embodiments, the cancer may have a HER2mutation. In some embodiments, the cancer may have a PI#K mutation. Insome embodiments, the cancer may have a B-Raf protein mutation.

In an embodiment, kits for administration of the combination therapy areprovided. In an embodiment, the kit includes separate pharmaceuticalcompositions containing the Hsp90 inhibitor according to formulae (I) or(Ia) or a compound in Tables 1 or 2, and a platinum-containinganti-cancer agent. In another embodiment, the kit includes onepharmaceutical composition containing both the Hsp90 inhibitor and theplatinum-containing anti-cancer agent. In any of these embodiments, eachpharmaceutical composition includes one or more pharmaceuticallyacceptable carrier or diluent. In any one of these embodiments, theplatinum-containing agent may be cisplatin, carboplatin, oxaliplatin, ortheir analogues. In any one of these embodiments, the Hsp90 inhibitormay be a compound represented in Tables 1 or 2. In any one of theseembodiments, the platinum-containing agent may be cisplatin.

In an embodiment, the invention provides the use of an Hsp90 inhibitoraccording to formulae (I) or (Ia) or a compound in Tables 1 or 2 for themanufacture of a medicament for treating cancer in combination with aplatinum-containing anti-cancer agent.

In an embodiment, a method of treating drug-resistant cancer in asubject includes administering to the subject an effective amount of thepharmaceutical combination including an Hsp90 compound according toformulae (I) or (Ia) or a compound in Tables 1 or 2 and aplatinum-containing anti-cancer agent. In an embodiment, the methodfurther includes the administration of one or more therapeutic agents.In certain embodiments, the combination treatment utilizes an Hsp90compound according to formulae (I) or (Ia) or a compound in Tables 1 or2 with a platinum-containing anti-cancer agent to help to arrest,partially or fully, or reduce the development of drug resistant cancerin a subject. The combinations described herein may allow a reduced doseof the platinum-containing agent given to a subject, because the Hsp90inhibitor should inhibit the development of multidrug-resistant cancercells. In an embodiment, the platinum-containing anti-cancer agent maybe cisplatin, carboplatin, oxaliplatin, or their derivatives. In anotherembodiment, the platinum-containing agent may be cisplatin.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of some embodiments of the invention, as illustrated in theaccompanying drawings. The drawings are not necessarily to scale,emphasis instead being placed upon illustrating the principles of theinvention.

FIG. 1 shows a dose-dependent curve with the IC₅₀ of ganetespib, atabout 32 nM.

FIG. 2 shows a dose-dependent curve with the IC₅₀ of cisplatin at about5.7 μM.

FIG. 3 shows significant killing of HCT-116 cells by ganetespib incombination with cisplatin. Cells were exposed to the indicated singleagent or combination, concurrently, for 3 days.

FIG. 4 shows significant killing of HCT-116 cells by the sequentialcombination of ganetespib with cisplatin. Cells were exposed toganetespib for 1 hour, washed and then treated with vehicle (DMSO) orindicated chemotherapeutic for 3 days. Single agent chemotherapeutic wasdosed for 3 days.

FIG. 5 shows substantial treatment improvement by a combination ofganetespib with cisplatin in an animal model of HCT-116 colon cancerxenograft. Ganetespib (150 mg/kg) was given as a single bolus injection6 hours prior to cisplatin (2 mg/kg) administration.

FIG. 6 shows substantial treatment improvement by a combination ofganetespib with cisplatin in an animal model of MDA-MB-231 breast cancertumor xenograft. Ganetespib (150 mg/kg) was given as a single bolusinjection 6 hours prior to cisplatin (2 mg/kg) administration.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term “alkyl” means a saturated or unsaturated,straight chain or branched, non-cyclic hydrocarbon having from 1 to 10carbon atoms. Representative straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyland n-decyl; while representative branched alkyls include isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl,2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, and the like. Theterm “(C₁-C₆)alkyl” means a saturated, straight chain or branched,non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Alkyl groupsincluded in compounds described herein may be optionally substitutedwith one or more substituents. Examples of unsaturated alkyls includevinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl,2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl,2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl,2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, acetylenyl,propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl,1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl,1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, andthe like. Alkyl groups included in compounds described herein may beoptionally substituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated or unsaturated,mono- or polycyclic, non-aromatic hydrocarbon having from 3 to 20 carbonatoms. Representative cycloalkyls include cyclopropyl,1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, octahydropentalenyl, cyclohexenyl,cyclooctenyl, cyclohexynyl, and the like. Cycloalkyl groups included incompounds described herein may be optionally substituted with one ormore substituents.

As used herein, the term “alkylene” refers to an alkyl group that hastwo points of attachment. The term “(C₁-C₆)alkylene” refers to analkylene group that has from one to six carbon atoms. Straight chain(C₁-C₆)alkylene groups are preferred. Non-limiting examples of alkylenegroups include methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), and the like. Alkylenegroups may be saturated or unsaturated, and may be optionallysubstituted with one or more substituents.

As used herein, the term “lower” refers to a group having up to fouratoms. For example, a “lower alkyl” refers to an alkyl radical havingfrom 1 to 4 carbon atoms, “lower alkoxy” refers to “—O—(C₁-C₄)alkyl.

As used herein, the term “haloalkyl” means an alkyl group, in which oneor more, including all, the hydrogen radicals are replaced by a halogroup(s), wherein each halo group is independently selected from —F,—Cl, —Br, and —I. For example, the term “halomethyl” means a methyl inwhich one to three hydrogen radical(s) have been replaced by a halogroup. Representative haloalkyl groups include trifluoromethyl,bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and thelike.

As used herein, an “alkoxy” is an alkyl group which is attached toanother moiety via an oxygen linker. Alkoxy groups included in compoundsdescribed herein may be optionally substituted with one or moresubstituents.

As used herein, a “haloalkoxy” is a haloalkyl group which is attached toanother moiety via an oxygen linker.

As used herein, the term an “aromatic ring” or “aryl” means a mono- orpolycyclic hydrocarbon, containing from 6 to 15 carbon atoms, in whichat least one ring is aromatic. Examples of suitable aryl groups includephenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl,as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. Aryl groups included in compounds describedherein may be optionally substituted with one or more substituents. Inan embodiment, the aryl group is a monocyclic ring, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl.”

As used herein, the term “aralkyl” means an aryl group that is attachedto another group by a (C₁-C₆)alkylene group. Representative aralkylgroups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like.Aralkyl groups included in compounds described herein may be optionallysubstituted with one or more substituents.

As used herein, the term “heterocyclyl” means a monocyclic or apolycyclic, saturated or unsaturated, non-aromatic ring or ring systemwhich typically contains 5- to 20-members and at least one heteroatom. Aheterocyclic ring system can contain saturated ring(s) or unsaturatednon-aromatic ring(s), or a mixture thereof. A 3- to 10-memberedheterocycle can contain up to 5 heteroatoms, and a 7- to 20-memberedheterocycle can contain up to 7 heteroatoms. Typically, a heterocyclehas at least one carbon atom ring member. Each heteroatom isindependently selected from nitrogen, which can be oxidized (e.g., N(O))or quaternized, oxygen and sulfur, including sulfoxide and sulfone. Theheterocycle may be attached via any heteroatom or carbon atom.Representative heterocycles include morpholinyl, thiomorpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatommay be substituted with a protecting group known to those of ordinaryskill in the art, for example, a nitrogen atom may be substituted with atert-butoxycarbonyl group. Furthermore, the heterocycle included incompounds described herein may be optionally substituted with one ormore substituents. Only stable isomers of such substituted heterocyclicgroups are contemplated in this definition.

As used herein, the term “heteroaryl”, or like terms, means a monocyclicor a polycyclic, unsaturated radical containing at least one heteroatom,in which at least one ring is aromatic. Polycyclic heteroaryl rings mustcontain at least one heteroatom, but not all rings of a polycyclicheteroaryl moiety must contain heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be oxidized (e.g., N(O))or quaternized, oxygen and sulfur, including sulfoxide and sulfone.Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl,furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl,oxazolyl, imidazolyl, thiazolyl, an isoxazolyl, quinolinyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl,triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl,benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl,benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl,tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl,pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,imidazo[1,2-a]pyridyl, and benzothienyl. In one embodiment, theheteroaromatic ring may be a 5-8 membered monocyclic heteroaryl ring.The point of attachment of a heteroaromatic or heteroaryl ring may be ateither a carbon atom or a heteroatom. Heteroaryl groups included incompounds described herein may be optionally substituted with one ormore substituents. As used herein, the term “(C₅)heteroaryl” means anheteroaromatic ring of 5 members, wherein at least one carbon atom ofthe ring is replaced with a heteroatom, such as, for example, oxygen,sulfur or nitrogen. Representative (C₅)heteroaryls include furanyl,thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and thelike. As used herein, the term “(C₆)heteroaryl” means an aromaticheterocyclic ring of 6 members, wherein at least one carbon atom of thering is replaced with a heteroatom such as, for example, oxygen,nitrogen or sulfur. Representative (C₆)heteroaryls include pyridyl,pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, and the like.

As used herein, the term “heteroaralkyl” means a heteroaryl group thatis attached to another group by a (C₁-C₆)alkylene. Representativeheteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl,imidazol-4-yl-methyl, and the like. Heteroaralkyl groups included incompounds described herein may be optionally substituted with one ormore substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, andheteroaralkyl groups include are those substituents which form a stablecompound described herein without significantly adversely affecting thereactivity or biological activity of the compound described herein.Examples of substituents for an alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, andheteroaralkyl include an alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl,heteroalkyl, alkoxy, (each of which can be optionally and independentlysubstituted), —C(O)NR²⁸R²⁹, —C(S)NR²⁸R²⁹, —C(NR³²)NR²⁸R²⁹, —NR³³C(O)R³¹,—NR³³C(S)R³¹, —NR³³C(NR³²)R³¹, halo, —OR³³, cyano, nitro, —C(O)R³³,—C(S)R³³, —C(NR³²)R³³, —NR²⁸R²⁹, —C(O)OR³³, —C(S)OR³³, —C(NR³²)OR³³,—OC(O)R³³, —OC(S)R³³, —OC(NR³²)R³³, —NR³⁰C(O)NR²⁸R²⁹, —NR³³C(S)NR²⁸R²⁹,—NR³³C(NR³²)NR²⁸R²⁹, —OC(O)NR²⁸R²⁹, —OC(S)NR²⁸R²⁹, —OC(NR³²)NR²⁸R²⁹,—NR³³C(O)OR³¹, —NR³³C(S)OR³¹, —NR³³C(NR³²)OR³¹, —S(O)_(k)R³³,—OS(O)_(k)R³³, —NR³³S(O)_(k)R³³, —S(O)_(k)NR²⁸R²⁹, —OS(O)_(k)NR²⁸R²⁹,—NR³³S(O)_(k)NR²⁸R²⁹, guanidino, —C(O)SR³¹, —C(S)SR³¹, —C(NR³²)SR³¹,—OC(O)OR³¹, —OC(S)OR³¹, —OC(NR³²)OR³¹, —SC(O)R³³, —SC(O)OR³¹,—SC(NR³²)OR³¹, —SC(S)R³³, —SC(S)OR³¹, —SC(O)NR²⁸R²⁹, —SC(NR³²)NR²⁸R²⁹,—SC(S)NR²⁸R²⁹, —SC(NR³²)R³³, —OS(O)_(k)OR³¹, —S(O)_(k)OR³¹,—NR³⁰S(O)_(k)OR³¹, —SS(O)_(k)R³³, —SS(O)_(k)OR³¹, —SS(O)_(k)NR²⁸R²⁹,—OP(O)(OR³¹)₂, or —SP(O)(OR³¹)₂. In addition, any saturated portion ofan alkyl, cycloalkyl, alkylene, heterocyclyl, alkenyl, cycloalkenyl,alkynyl, aralkyl and heteroaralkyl groups, may also be substituted with═O, ═S, or ═N—R³². Each R²⁸ and R²⁹ is independently H, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, orheteroalkyl represented by R²⁸ or R²⁹ is optionally and independentlysubstituted. Each R³⁰, R³¹ and R³³ is independently H, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, andheteraralkyl represented by R³⁰ or R³¹ or R³³ is optionally andindependently unsubstituted. Each R³² is independently H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteraralkyl, —C(O)R³³, —C(O)NR²⁸R²⁹, —S(O)_(k)R³³,or —S(O)_(k)NR²⁸R²⁹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteraralkylrepresented by R³² is optionally and independently substituted. Thevariable k is 0, 1 or 2. In some embodiments, suitable substituentsinclude C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,C₁-C₄ hydroxyalkyl, halo, or hydroxyl.

When a heterocyclyl, heteroaryl or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent, thenitrogen may be oxidized or a quaternary nitrogen.

Unless indicated otherwise, the compounds described herein containingreactive functional groups, such as, for example, carboxy, hydroxy,thiol and amino moieties, also include corresponding protectedderivatives thereof. “Protected derivatives” are those compounds inwhich a reactive site or sites are blocked with one or more protectinggroups. Examples of suitable protecting groups for hydroxyl groupsinclude benzyl, methoxymethyl, allyl, trimethylsilyl,tert-butyldimethylsilyl, acetate, and the like. Examples of suitableamine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl,tert-butyl, benzyl and fluorenylmethyloxy-carbonyl (Fmoc). Examples ofsuitable thiol protecting groups include benzyl, tert-butyl, acetyl,methoxymethyl and the like. Other suitable protecting groups are wellknown to those of ordinary skill in the art and include those found inT. W. GREENE, PROTECTING GROUPS IN ORGANIC SYNTHESIS, (John Wiley &Sons, Inc., 1981).

As used herein, the term “compound(s) described herein” or similar termsrefers to a compound of formulae (I), or (Ia) or a compound in Tables 1or 2 or a tautomer or pharmaceutically acceptable salt thereof. Alsoincluded in the scope of the embodiments are a solvate, clathrate,hydrate, polymorph, prodrug, or protected derivative of a compound offormulae (I), or (Ia), or a compound in Tables 1 or 2.

The compounds described herein may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Each chemical structure shown herein, including thecompounds described herein, encompass all of the correspondingcompound's enantiomers, diastereomers and geometric isomers, that is,both the stereochemically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and isomeric mixtures(e.g., enantiomeric, diastereomeric and geometric isomeric mixtures). Insome cases, one enantiomer, diastereomer or geometric isomer willpossess superior activity or an improved toxicity or kinetic profilecompared to other isomers. In those cases, such enantiomers,diastereomers and geometric isomers of compounds described herein arepreferred.

When a disclosed compound is named or depicted by structure, it is to beunderstood that solvates (e.g., hydrates) of the compound or apharmaceutically acceptable salt thereof is also included. “Solvates”refer to crystalline forms wherein solvent molecules are incorporatedinto the crystal lattice during crystallization. Solvates may includewater or nonaqueous solvents such as ethanol, isopropanol, DMSO, aceticacid, ethanolamine and ethyl acetate. When water is the solvent moleculeincorporated into the crystal lattice of a solvate, it is typicallyreferred to as a “hydrate”. Hydrates include stoichiometric hydrates aswell as compositions containing variable amounts of water.

When a disclosed compound is named or depicted by structure, it is to beunderstood that the compound, including solvates thereof, may exist incrystalline forms, non-crystalline forms or a mixture thereof. Thecompounds or solvates may also exhibit polymorphism (i.e., the capacityto occur in different crystalline forms). These different crystallineforms are typically known as “polymorphs.” It is to be understood thatwhen named or depicted by structure, the disclosed compounds andsolvates (e.g., hydrates) also include all polymorphs thereof.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement and other descriptive properties of thecrystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra and X-ray powder diffractionpatterns, which may be used for identification. One of ordinary skill inthe art will appreciate that different polymorphs may be produced, forexample, by changing or adjusting the conditions used in crystallizingthe compound. For example, changes in temperature, pressure or solventmay result in different polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

When a disclosed compound is named or depicted by structure, it is to beunderstood that clathrates (“inclusion compounds”) of the compound orits pharmaceutically acceptable salt, solvate or polymorph, are alsoincluded. “Clathrate” means a compound described herein, or a saltthereof, in the form of a crystal lattice that contains spaces (e.g.,channels) that have a guest molecule trapped within (e.g., a solvent orwater).

As used herein, and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound described herein. Prodrugs may become active upon such reactionunder biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated herein includeanalogs or derivatives of compounds of formulae (I) or (Ia) or acompound in Tables 1 or 2 that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides andphosphate analogues. Prodrugs can typically be prepared using well-knownmethods, such as those described by BURGER'S MEDICINAL CHEMISTRY ANDDRUG DISCOVERY, (Manfred E. Wolff Ed., 5^(h) ed. (1995)) 172-178,949-982.

The articles “a”, “an” and “the” are used herein to refer to one or tomore than one (i.e., to at least one) of the grammatical object of thearticle unless otherwise clearly indicated by contrast. By way ofexample, “an element” means one element or more than one element.

The term “including” is used herein to mean, and is used interchangeablywith, the phrase “including but not limited to”.

The term “or” is used herein to mean, and is used interchangeably with,the term “and/or,” unless context clearly indicates otherwise.

The term “such as” is used herein to mean, and is used interchangeably,with the phrase “such as but not limited to”.

Unless specifically stated or obvious from context, as used herein, theterm “about” is understood as within a range of normal tolerance in theart, for example within 2 standard deviations of the mean. About can beunderstood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear fromcontext, all numerical values provided herein can be modified by theterm about.

As used herein, the terms “subject”, “patient” and “mammal” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),preferably a mammal including a non-primate (e.g., a cow, pig, horse,sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate(e.g., a monkey, chimpanzee and a human), and more preferably a human.In an embodiment, the subject is a non-human animal such as a farmanimal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat,guinea pig or rabbit). In another embodiment, the subject is a human.

As used herein, “Hsp90” includes each member of the family of heat shockproteins having a mass of about 90-kiloDaltons. For example, in humansthe highly conserved Hsp90 family includes the cytosolic Hsp90a andHsp90β isoforms, as well as GRP94, which is found in the endoplasmicreticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix.

The term “c-Kit” or “c-Kit kinase” refers to a membrane receptor proteintyrosine kinase which is preferably activated upon binding Stem CellFactor (SCF) to its extracellular domain. Yarden, et al., Embo. J.,(1987) 11:3341-3351; Qiu, et al., Embo. J., (1988) 7:1003-1011. The fulllength amino acid sequence of a c-Kit kinase preferably is as set forthin Yarden, et al.; and Qiu, et al., which are incorporated by referenceherein in their entirety. Mutant versions of c-Kit kinase areencompassed by the term “c-Kit” or “c-Kit kinase” and include those thatfall into two classes: (1) having a single amino acid substitution atcodon 816 of the human c-Kit kinase, or its equivalent position in otherspecies (Ma, et al., J. Invest Dermatol., (1999) 112:165-170), and (2)those which have mutations involving the putative juxtamembrane z-helixof the protein (Ma, et al., J. Biol. Chem., (1999) 274:13399-13402).Both of these publications are incorporated by reference herein in theirentirety, including any drawings.

As used herein, “BCR-ABL” is a fusion protein that results from thetranslocation of gene sequences from c-ABL protein tyrosine kinase onchromosome 9 into BCR sequences on chromosome 22 producing thePhiladelphia chromosome. A schematic representation of human BCR, ABLand BCR-ABL can be seen in FIG. 1 of U.S. patent application Ser. No.10/193,651, filed on Jul. 9, 2002. Depending on the breaking point inthe BCR gene, BCR-ABL fusion proteins can vary in size from 185-230 kDbut they must contain at least the OLI domain from BCR and the TK domainfrom ABL for transforming activity. The most common BCR-ABL geneproducts found in humans are P230 BCR-ABL, P210 BCR-ABL and P190BCR-ABL. P210 BCR-ABL is characteristic of CML and P190 BCR-ABL ischaracteristic of ALL.

FLT3 kinase is a tyrosine kinase receptor involved in the regulation andstimulation of cellular proliferation. Gilliland, et al., Blood (2002),100:1532-42. The FLT3 kinase has five immunoglobulin-like domains in itsextracellular region, as well as an insert region of 75-100 amino acidsin the middle of its cytoplasmic domain. FLT3 kinase is activated uponthe binding of the FLT3 ligand which causes receptor dimerization.Dimerization of the FLT3 kinase by FLT3 ligand activates theintracellular kinase activity as well as a cascade of downstreamsubstrates including Stat5, Ras, phosphatidylinositol-3-kinase (PI3K),Erk2, Akt, MAPK, SHC, SHP2 and SHIP. Rosnet, et al., Acta Haematol.(1996), 95:218; Hayakawa, et al., Oncogene (2000), 19:624; Mizuki, etal., Blood (2000), 96:3907; Gilliand, et al., Curr. Opin. Hematol.(2002), 9: 274-81. Both membrane-bound and soluble FLT3 ligand bind,dimerize, and subsequently activate the FLT3 kinase.

Normal cells that express FLT3 kinase include immature hematopoieticcells, typically CD34+ cells, placenta, gonads and brain. Rosnet, etal., Blood (1993), 82:1110-19; Small, et al., Proc. Natl. Acad. Sci.U.S.A. (1994), 91:459-63; Rosnet, et al., Leukemia (1996), 10:238-48.However, efficient stimulation of proliferation via FLT3 kinasetypically requires other hematopoietic growth factors or interleukins.FLT3 kinase also plays a critical role in immune function through itsregulation of dendritic cell proliferation and differentiation. McKenna,et al., Blood (2000), 95:3489-497. Numerous hematologic malignanciesexpress FLT3 kinase, the most prominent of which is AML. Yokota, et al.,Leukemia (1997), 11:1605-09. Other FLT3 expressing malignancies includeB-precursor cell acute lymphoblastic leukemias, myelodysplasticleukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenousleukemias. Rasko, et al., Leukemia (1995), 9:2058-66.

FLT3 kinase mutations associated with hematologic malignancies areactivating mutations. In other words, the FLT3 kinase is constitutivelyactivated without the need for binding and dimerization by FLT3 ligand,and therefore stimulates the cell to grow continuously. Two types ofactivating mutations have been identified: internal tandem duplications(ITDs) and point mutation in the activating loop of the kinase domain.As used herein, the term “FLT3 kinase” refers to both wild type FLT3kinase and mutant FLT3 kinases, such as FLT3 kinases that haveactivating mutations. Compounds provided herein are useful in treatingconditions characterized by inappropriate FLT3 activity, such asproliferative disorders. Inappropriate FLT3 activity includes enhancedFLT3 activity resulting from increased or de novo expression of FLT3 incells, increased FLT3 expression or activity, and FLT3 mutationsresulting in constitutive activation. The existence of inappropriate orabnormal FLT3 ligand and FLT3 levels or activity can be determined usingwell-known methods in the art. For example, abnormally high FLT3 levelscan be determined using commercially available ELISA kits. FLT3 levelscan also be determined using flow cytometric analysis,immunohistochemical analysis and in situ hybridization techniques.

“Epidermal growth factor receptor” or “EGFR”, as used herein, means anyepidermal growth factor receptor (EGFR) protein, peptide, or polypeptidehaving EGFR or EGFR family activity (e.g., Her1, Her2, Her3 and/orHer4), such as encoded by EGFR Genbank Accession Nos. shown in Table Iof U.S. patent application Ser. No. 10/923,354, filed on Aug. 20, 2004,or any other EGFR transcript derived from a EGFR gene and/or generatedby EGFR translocation. The term “EGFR” is also meant to include otherEGFR proteins, peptides, or polypeptides derived from EGFR isoforms(e.g., Her1, Her2, Her3 and/or Her4), mutant EGFR genes, splice variantsof EGFR genes, and EGFR gene polymorphisms.

EGFR is a member of the type 1 subgroup of receptor tyrosine kinasefamily of growth factor receptors which play critical roles in cellulargrowth, differentiation and survival. Activation of these receptorstypically occurs via specific ligand binding which results in hetero- orhomodimerization between receptor family members, with subsequentautophosphorylation of the tyrosine kinase domain. Specific ligandswhich bind to EGFR include epidermal growth factor (EGF), transforminggrowth factor α (TGFα), amphiregulin and some viral growth factors.Activation of EGFR triggers a cascade of intracellular signalingpathways involved in both cellular proliferation (the ras/raf/MAP kinasepathway) and survival (the PI3 kinase/Akt pathway). Members of thisfamily, including EGFR and HER2, have been directly implicated incellular transformation.

A number of human malignancies are associated with aberrant oroverexpression of EGFR and/or overexpression of its specific ligands.Gullick, Br. Med. Bull. (1991), 47:87-98; Modijtahedi & Dean, Int. J.Oncol. (1994), 4:277-96; Salomon, et al., Crit. Rev. Oncol. Hematol.(1995), 19:183-232. Aberrant or overexpression of EGFR has beenassociated with an adverse prognosis in a number of human cancers,including head and neck, breast, colon, prostate, lung (e.g., NSCLC,adenocarcinoma and squamous lung cancer), ovarian, gastrointestinalcancers (gastric, colon, pancreatic), renal cell cancer, bladder cancer,glioma, gynecological carcinomas and prostate cancer. In some instances,overexpression of tumor EGFR has been correlated with bothchemoresistance and a poor prognosis. Lei, et al., Anti-cancer Res.(1999), 19:221-28; Veale, et al., Br. J. Cancer (1993); 68:162-65.Mutations in EGFR are associated with many types of cancer as well. Forexample, EGFR mutations are highly prevalent in non-mucinous BACpatients. Finberg, et al., J. Mol. Diagnostics (2007) 9(3):320-26.

c-Met is a receptor tyrosine kinase that is encoded by the Metprotooncogene and transduces the biological effects of hepatocyte growthfactor (HGF), which is also referred to as scatter factor (SF). Jiang etal., Crit. Rev. Oncol. Hemtol. 29: 209-248 (1999), the entire teachingsof which are incorporated herein by reference. c-Met and HGF areexpressed in numerous tissues, although their expression is normallyconfined predominantly to cells of epithelial and mesenchymal origin,respectively. c-Met and HGF are required for normal mammaliandevelopment and have been shown to be important in cell migration, cellproliferation and survival, morphogenic differentiation, andorganization of 3-dimensional tubular structures (e.g., renal tubularcells, gland formation, etc.). The c-Met receptor has been shown to beexpressed in a number of human cancers. c-Met and its ligand, HGF, havealso been shown to be co-expressed at elevated levels in a variety ofhuman cancers (particularly sarcomas). However, because the receptor andligand are usually expressed by different cell types, c-Met signaling ismost commonly regulated by tumor-stroma (tumor-host) interactions.Furthermore, c-Met gene amplification, mutation, and rearrangement havebeen observed in a subset of human cancers. Families with germinemutations that activate c-Met kinase are prone to multiple kidney tumorsas well as tumors in other tissues. Numerous studies have correlated theexpression of c-Met and/or HGF/SF with the state of disease progressionof different types of cancer (including lung, colon, breast, prostate,liver, pancreas, brain, kidney, ovaries, stomach, skin, and bonecancers). Furthermore, the overexpression of c-Met or HGF have beenshown to correlate with poor prognosis and disease outcome in a numberof major human cancers including lung, liver, gastric, and breast.

The anaplastic lymphoma kinase (ALK) tyrosine kinase receptor is anenzyme that, in humans, is encoded by the ALK gene. The 2;5 chromosomaltranslocation is frequently associated with anaplastic large celllymphomas (ALCLs). The translocation creates a fusion gene consisting ofthe ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM)gene: the 3′ half of ALK, derived from chromosome 2, is fused to the 5′portion of NPM from chromosome 5. The product of the NPM-ALK fusion geneis oncogenic. Other possible translocations of the ALK gene, such as theeml4 translocation, are also implicated in cancer.

The general role of ALK in cancer has been described. See, e.g., Pulfordet al., J. Cell Physiol. 199(3): 330-358 (2004). Abnormalities in theanaplastic lymphoma kinase (ALK) gene have an established pathogenicrole in many pediatric and adult cancers, including non-small cell lungcancer (NSCLC), diffuse large B-cell lymphoma (DLBCL), anaplastic largecell lymphoma (ALCL), neuroblastoma (NBL), and inflammatorymyofibroblastic tumors (IMT), non-Hodgkin's lymphoma (NHL), andesophageal squamous cell carcinoma (ESCC). These diseases account formore than 250,000 new cancer diagnoses each year in the United Statesalone.

More particularly, EML4-ALK and KIF5B-ALK translocations have been foundin non-small cell lung cancer. See. e.g. Mano H., Cancer Sci. 2008December; 99(12):2349-55; Takeuchi K et al., Clin Cancer Res. 2009 May1; 15(9):3143-9. CLTC-ALK mutation has been found in DLBCL. See e.g.Rudzki Z et al., Pol J Pathol. 2005; 56 (1):37-45. NPM-ALK, MSN-ALK, andother mutations have been found in ALCL. See e.g. Lamant L et al., GenesChromosomes Cancer. 2003 August; 37 (4):427-32; Webb T R et al. ExpertRev Anticancer Ther 2009 March; 9(3):331-56. TPM4-ALK mutation has beenfound in esophageal squamous cell carcinoma (ESCC). See e.g. Li R,Morris S W., Med Res Rev. 2008 May; 28 (3):372-412. F1174L, R1275Q, andother point mutations have been found in NBL. See e.g. van Roy N et al.Genome Med 2009 Jul. 27; 1 (7):74. TPM3-ALK, TPM4-ALK, CLTC-ALK,RanBP2-ALK, and TPM4-ALK mutations have been found in IMT. See e.g.Gleason B C, Hornick J L. J Clin Pathol 2008 April; 61(4):428-37. Themethods of detection and identification of these alterations, mutationsor rearrangements in an ALK gene or gene product can be found in theabove-identified references and references cited therein.

The KRAS oncogene (the cellular homolog of the Kirsten rat sarcoma virusgene) is a critical gene in the development of a variety of cancers, andthe mutation status of this gene is an important characteristic of manycancers. Mutation status of the gene can provide diagnostic, prognosticand predictive information for several cancers. The KRAS gene is amember of a family of genes (KRAS, NRAS and HRAS). KRAS is a member ofthe RAS family of oncogenes, a collection of small guanosinetriphosphate (GTP)-binding proteins that integrate extracellular cuesand activate intracellular signaling pathways to regulate cellproliferation, differentiation, and survival. Gain-of-function mutationsthat confer transforming capacity are frequently observed in KRAS,predominantly arising as single amino acid substitutions at amino acidresidues G12, G13 or Q61. Constitutive activation of KRAS leads to thepersistent stimulation of downstream signaling pathways that promotetumorigenesis, including the RAF/MEK/ERK and PI3K/AKT/mTOR cascades. InNSCLC, KRAS mutations are highly prevalent (20-30%) and are associatedwith unfavorable clinical outcomes. Mutations in KRAS appear mutuallyexclusive with those in EGFR in NSCLC tumors; more importantly, they canaccount for primary resistance to targeted EGFR TKI therapies. Mutationsin the KRAS gene are common in many types of cancer, includingpancreatic cancer (˜65%), colon cancer (˜40%), lung cancer (˜20%) andovarian cancer (˜15%).

The methods and procedures for the detections and/or identifications ofEGFR, KRAS, and/or ALK over-expressions and/or mutations are known inthe literature and can be easily carried out by a skilled person. See,e.g., U.S. Pat. Nos. 7,700,339; 5,529,925; 5,770,421; U.S. PatentApplication Publication No. US2011/0110923; Palmer et al, Biochem. J.(2009), 345-361; Koivunen et al, Clin. Can. Res., 2008, 14, 4275-4283;Anderson, Expert Rev. Mol. Diagn. 11(6), 635-642 (2011); Pinto et al,Cancer Genetics 204 (2011), 439-446; Rekhtman et al; Clin Cancer Res2012; 18:1167-1176; Massarelli et al, Clin Cancer Res 2007;13:2890-2896; Lamy et al, Modern Pathology (2011) 24, 1090-1100;Balschun et al, Expert Rev. Mol. Diagn. 11(8), 799-802 (2011); Vakianiet al, J Pathol 2011; 223, 219-229; Okudela et al, PathologyInternational 2010; 60: 651-660; John et al, Oncogene (2009) 28,S14-S23; Jimeno et al, J. Clin. Oncol. 27, 1130-1135 (2009); Van Kriekenet al, Virchows Archiv. 453, 417-431 (2008); and the references cited inthe-above identified references. Thresholds of increased expression thatconstitute an EGFR mutation or an ALK mutation are well known in theart. Moreover, it is generally recognized that once an EGFR mutation isdetected in a cancer, the KRAS mutation will be eliminated in the samecancer. Put reversely, if a KRAS mutation is positively identified in acancer from a subject, it is then not necessary to engage in any furtherEGFR-related identification. Similar principle can be applied to an ALKmutation in a cancer. That is if there is an ALK mutation detected in acancer, it is extremely rare that an EGFR or KRAS mutation will beimplicated. Stated another way, once an ALK mutation is positivelyidentified in a cancer, no further identification is necessary eitherfor EGFR mutation or for KRAS mutation in the same cancer.

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy, (e.g.,diabetic retinopathy or other retinopathies), cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis and desmoidtumors. Non-cancerous proliferative disorders also includehyperproliferation of cells in the skin such as psoriasis and its variedclinical forms, Reiter's syndrome, pityriasis rubra pilaris,hyperproliferative variants of disorders of keratinization (e.g.,actinic keratosis, senile keratosis), scleroderma, and the like. In anembodiment, the proliferative disorder is cancer.

In an embodiment, the invention provides a method of treating aproliferative disorder in a subject, comprising administering to thesubject an effective amount of the combination of Hsp90 inhibitor andplatinum-containing anti-cancer agent as described herein. In anembodiment, the proliferative disorder is cancer. In an embodiment, thecancer is breast cancer, gastric cancer, colorectal cancer, pancreaticcancer, ocular melanoma, prostate cancer, gastrointestinal stromaltumors (GIST), advanced esophagogastric cancer, melanoma, hepatocellularcancer, solid tumor, liver cancer, head and neck cancer, small cell lungcancer, non-small cell lung cancer, bladder cancer, testicular tumor,ovarian cancer, lymphoma, leukemia, multiple myeloma, or colon cancer.In an embodiment, the cancer is solid cancer, gastric cancer, bladdercancer, ovarian cancer, or colorectal cancer. In an embodiment, thecancer is colon cancer. In an embodiment, the cancer is metastaticcolorectal cancer. In an embodiment, the cancer is bladder cancer. In anembodiment, the cancer is solid cancer. In an embodiment, the cancer isgastric cancer. In an embodiment, the cancer may have a mutation ortranslocation in EGFR, K-Ras, PI3K, ALK, HER2 and/or B-Raf proteins.

Some of the disclosed methods can be particularly effective at treatingsubjects whose cancer has become “drug resistant” or “multi-drugresistant”. A cancer which initially responded to an anti-cancer drugbecomes resistant to the anti-cancer drug when the anti-cancer drug isno longer effective in treating the subject with the cancer. Forexample, many tumors will initially respond to treatment with ananti-cancer drug by decreasing in size or even going into remission,only to develop resistance to the drug. “Drug resistant” tumors arecharacterized by a resumption of their growth and/or reappearance afterhaving seemingly gone into remission, despite the administration ofincreased dosages of the anti-cancer drug. Cancers that have developedresistance to two or more anti-cancer drugs are said to be “multi-drugresistant”. For example, it is common for cancers to become resistant tothree or more anti-cancer agents, often five or more anti-cancer agentsand at times ten or more anti-cancer agents.

Other anti-proliferative or anti-cancer therapies may be combined withthe pharmaceutical combination of this invention to treat proliferativediseases and cancer. Other therapies or anti-cancer agents that may beused in combination with the inventive anti-cancer agents of the presentinvention include surgery, radiotherapy (including, but not limited to,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes),endocrine therapy, biologic response modifiers (including, but notlimited to, interferons, interleukins, and tumor necrosis factor (TNF)),hyperthermia and cryotherapy, agents to attenuate any adverse effects(e.g., antiemetics), and other approved chemotherapeutic drugs. In anembodiment, the pharmaceutical combination of the invention isadministered with one or more therapeutic agent selected from DFMO,vandetanib, trastuzumab, temodar, dexamethasone, epirubicin, ifosfamide,mitoxantrone, vorinostat, interferon alpha, rituximab, prednisone,cyclophosphamide, bendamustine, adriamycin, valproate, celecoxib,thalidomide, nelarabine, methotrexate, filgrastim, gemtuzumabozogamicin, testosterone, clofarabine, cytarabine, everolimus,rituxumab, busulfan, capecitabine, pegfilgrastim, mesna, amrubicin,obatoclax, gefitinib, cyclosporine, dasatinib, temozolomide, thiotepa,plerixafor, mitotane, vincristine, doxorubicin, cixutumumab, endostar,fenofibrate, melphalan, sunitinib, rubitecan, enoxaparin, isotretinoin,tariquidar, pomalidomide, sorafenib, altretamine, idarubicin, rapamycin,zevalin, everolimus, pravastatin, carmustine, nelfinavir, streptozocin,tirapazamine, aprepitant, lenalidomide, G-CSF, procarbazine,alemtuzumab, amifostine, valspodar, lomustine, oblimersen, temsirolimus,vinblastine, figitumumab, belinostat, niacinamide, tipifarnib,estramustine, erlotinib, bevacizumab, paclitaxel, docetaxel, Abraxane®,pemetrexed, bortezomib, cetuximab, gemcitabine, 5-fluorouracil,leucovorin and tetracycline. In an embodiment, the one or moretherapeutic agent is selected from erlotinib, bevacizumab, bortezomib,paclitaxel, doxorubicin, docetaxel, mitoxantrone, cytarabine,5-fluorouracil, leucovorin, pemetrexed and vincristine.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from a compound of formulae (I) or (Ia) or a compound inTables 1 or 2 having an acidic functional group, such as a carboxylicacid functional group, and a pharmaceutically acceptable inorganic ororganic base. Suitable bases include hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of formulae (I) or (Ia) or a compound in Tables1 or 2 having a basic functional group, such as an amine functionalgroup, and a pharmaceutically acceptable inorganic or organic acid.Suitable acids include hydrogen sulfate, citric acid, acetic acid,oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogeniodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid,isonicotinic acid, oleic acid, tannic acid, pantothenic acid, saccharicacid, lactic acid, salicylic acid, tartaric acid, bitartratic acid,ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid,gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamicacid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,pamoic acid and p-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more pharmaceuticallyacceptable solvent molecules to one of the compounds of formulae (I) or(Ia) or a compound in Tables 1 or 2. The term “solvate” includeshydrates, e.g., hemihydrate, monohydrate, dihydrate, trihydrate,tetrahydrate, and the like.

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compound(s)described herein. The pharmaceutically acceptable carriers should bebiocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic anddevoid of other undesired reactions upon the administration to asubject. Standard pharmaceutical formulation techniques can be employed,such as those described in REMINGTON, J. P., REMINGTON'S PHARMACEUTICALSCIENCES (Mack Pub. Co., 17^(th) ed., 1985). Suitable pharmaceuticalcarriers for parenteral administration include, for example, sterilewater, physiological saline, bacteriostatic saline (saline containingabout 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank'ssolution, Ringer's-lactate, and the like. Methods for encapsulatingcompositions, such as in a coating of hard gelatin or cyclodextran, areknown in the art. See BAKER, ET AL., CONTROLLED RELEASE OF BIOLOGICALACTIVE AGENTS, (John Wiley and Sons, 1986).

As used herein, the term “effective amount” refers to an amount of acompound described herein which is sufficient to reduce or amelioratethe severity, duration, progression, or onset of a disease or disorder,delay onset of a disease or disorder, retard or halt the advancement ofa disease or disorder, cause the regression of a disease or disorder,prevent or delay the recurrence, development, onset or progression of asymptom associated with a disease or disorder, or enhance or improve thetherapeutic effect(s) of another therapy. In an embodiment of theinvention, the disease or disorder is a proliferative disorder. Theprecise amount of compound administered to a subject will depend on themode of administration, the type and severity of the disease orcondition and on the characteristics of the subject, such as generalhealth, age, sex, body weight and tolerance to drugs. For example, for aproliferative disease or disorder, determination of an effective amountwill also depend on the degree, severity and type of cell proliferation.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. When co-administered with othertherapeutic agents, e.g., when co-administered with an anti-canceragent, an “effective amount” of any additional therapeutic agent(s) willdepend on the type of drug used. Suitable dosages are known for approvedtherapeutic agents and can be adjusted by the skilled artisan accordingto the condition of the subject, the type of condition(s) being treatedand the amount of a compound of the invention being used. In cases whereno amount is expressly noted, an effective amount should be assumed.Non-limiting examples of an effective amount of a compound describedherein are provided herein below. In a specific embodiment, theinvention provides a method of treating, managing, or ameliorating adisease or disorder, e.g. a proliferative disorder, or one or moresymptoms thereof, the method comprising administering to a subject inneed thereof a dose of the Hsp90 inhibitor at least 150 μg/kg, at least250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, atleast 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg,at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least200 mg/kg or more of one or more compounds described herein once everyday, once every 2 days, once every 3 days, once every 4 days, once every5 days, once every 6 days, once every 7 days, once every 8 days, onceevery 10 days, once every two weeks, once every three weeks, or once amonth.

The dosage of the individual platinum-containing anti-cancer agent usedin the pharmaceutical combination may be equal to or lower than the doseof an individual therapeutic agent when given independently to treat,manage, or ameliorate a disease or disorder, or one or more symptomsthereof. In an embodiment of the invention, the disease or disorderbeing treated with a combination therapy is a proliferative disorder. Inan embodiment, the proliferative disorder is cancer. In an embodiment,the platinum-containing anticancer agent cisplatin is administered IV ata dose of between about 20 mg/m² to about 150 mg/m². In an embodiment,cisplatin is administered once daily. In an embodiment, cisplatin isadministered IV at 20 mg/m² once daily. In an embodiment, cisplatin isadministered IV at a dose of between about 75 mg/m² to about 100 mg/m².A treatment cycle can last between one and 6 weeks. The recommendeddosages of therapeutic agents currently used for the treatment,management, or amelioration of a disease or disorder, or one or moresymptoms thereof, can obtained from any reference in the art. For a morein depth review of dosage and treatment schedules for various disorders,see, e.g., GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF BASIS OFTHERAPEUTICS 9^(Th) ED, (Hardman, et al., Eds., NY:Mc-Graw-Hill (1996));PHYSICIAN'S DESK REFERENCE 57TH ED. (Medical Economics Co., Inc.,Montvale, N.J. (2003)).

As used herein, the terms “treat”, “treatment”, “inhibiting”, and“treating” refer to the reduction or amelioration of the progression,severity and/or duration of a disease or disorder, delay of the onset ofa disease or disorder, or the amelioration of one or more symptoms(preferably, one or more discernible symptoms) of a disease or disorder,resulting from the administration of one or more therapies (e.g., one ormore therapeutic agents such as a compound of the invention). The terms“treat”, “treatment” and “treating” also encompass the reduction of therisk of developing a disease or disorder, and the delay or inhibition ofthe recurrence of a disease or disorder. In an embodiment, the diseaseor disorder being treated is a proliferative disorder such as cancer. Inspecific embodiments, the terms “treat”, “treatment” and “treating”refer to the amelioration of at least one measurable physical parameterof a disease or disorder, such as growth of a tumor, not necessarilydiscernible by the patient. In other embodiments the terms “treat”,“treatment” and “treating” refer to the inhibition of the progression ofa disease or disorder, e.g., a proliferative disorder, either physicallyby the stabilization of a discernible symptom, physiologically by thestabilization of a physical parameter, or both. In another embodiment,the terms “treat”, “treatment” and “treating” of a proliferative diseaseor disorder refers to the reduction or stabilization of tumor size orcancerous cell count, and/or delay of tumor formation. In anotherembodiment, the terms “treat”, “treating” and “treatment” also encompassthe administration of a compound described herein as a prophylacticmeasure to patients with a predisposition (genetic or environmental) toany disease or disorder described herein.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) that can be used in the treatment of a disease ordisorder, e.g. a proliferative disorder, or one or more symptomsthereof. In certain embodiments, the term “therapeutic agent” refers toa compound described herein. In certain other embodiments, the term“therapeutic agent” does not refer to a compound described herein.Preferably, a therapeutic agent is an agent that is known to be usefulfor, or has been or is currently being used for the treatment of adisease or disorder, e.g., a proliferative disorder, or one or moresymptoms thereof.

As used herein, the term “synergistic” refers to a combination of acompound described herein and another therapeutic agent, which, whentaken together, is more effective than the additive effects of theindividual therapies. A synergistic effect of a combination of therapies(e.g., a combination of therapeutic agents) permits the use of lowerdosages of one or more of the therapeutic agent(s) and/or less frequentadministration of the agent(s) to a subject with a disease or disorder,e.g., a proliferative disorder. The ability to utilize lower the dosageof one or more therapeutic agent and/or to administer the therapeuticagent less frequently reduces the toxicity associated with theadministration of the agent to a subject without reducing the efficacyof the therapy in the treatment of a disease or disorder. In addition, asynergistic effect can result in improved efficacy of agents in theprevention, management or treatment of a disease or disorder, e.g. aproliferative disorder. Finally, a synergistic effect of a combinationof therapies may avoid or reduce adverse or unwanted side effectsassociated with the use of either therapeutic agent alone.

As used herein, the phrase “side effects” encompasses unwanted andadverse effects of a therapeutic agent. Side effects are alwaysunwanted, but unwanted effects are not necessarily adverse. An adverseeffect from a therapeutic agent might be harmful or uncomfortable orrisky to a subject. Side effects include fever, chills, lethargy,gastrointestinal toxicities (including gastric and intestinalulcerations and erosions), nausea, vomiting, neurotoxicities,nephrotoxicities, renal toxicities (including such conditions aspapillary necrosis and chronic interstitial nephritis), hepatictoxicities (including elevated serum liver enzyme levels),myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

As used herein, the term “in combination” refers to the use of more thanone therapeutic agent. The use of the term “in combination” does notrestrict the order in which the therapeutic agents are administered to asubject with a disease or disorder, e.g., a proliferative disorder. Afirst therapeutic agent, such as a compound described herein, can beadministered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second therapeutic agent, suchas an anti-cancer agent, to a subject with a disease or disorder, e.g. aproliferative disorder, such as cancer. In an embodiment, the Hsp90inhibitor and the platinum-containing anti-cancer agent are dosed onindependent schedules. In another embodiment, the Hsp90 inhibitor andthe platinum-containing anti-cancer agent are dosed on approximately thesame schedule. In another embodiment, the Hsp90 inhibitor and theplatinum-containing anticancer agent are dosed concurrently orsequentially on the same day.

As used herein, the terms “therapies” and “therapy” can refer to anyprotocol(s), method(s), and/or agent(s) that can be used in theprevention, treatment, management, or amelioration of a disease ordisorder, e.g., a proliferative disorder, or one or more symptomsthereof.

A used herein, a “protocol” includes dosing schedules and dosingregimens. The protocols herein are methods of use and includetherapeutic protocols.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a “racemic mixture” means about 50% of one enantiomerand about 50% of is corresponding enantiomer of the molecule. Thecombination encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds described herein.Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or diastereomers by well-known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

The compounds described herein are defined by their chemical structuresand/or chemical names. Where a compound is referred to by both achemical structure and a chemical name, and the chemical structure andthe chemical name conflict, the chemical structure is determinative ofthe compound's identity.

When administered to a subject (e.g., a non-human animal for veterinaryuse or for improvement of livestock or to a human for clinical use), thecompounds described herein are administered in an isolated form, or asthe isolated form in a pharmaceutical composition. As used herein,“isolated” means that the compounds described herein are separated fromother components of either: (a) a natural source, such as a plant orcell, preferably bacterial culture, or (b) a synthetic organic chemicalreaction mixture. Preferably, the compounds described herein arepurified via conventional techniques. As used herein, “purified” meansthat when isolated, the isolate contains at least 95%, preferably atleast 98%, of a compound described herein by weight of the isolateeither as a mixture of stereoisomers, or as a diastereomerically orenantiomerically pure isolate.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

The methods described herein utilize triazolone compounds listed inTables 1 or 2, or a compound represented by Formulae (I) or (Ia):

or a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

-   -   Z is OH, SH, or NH₂;    -   X is CR₄ or N;    -   R₁ is —H, —OH, —SH, an optionally substituted alkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, halo, cyano, nitro,        guanidino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy,        a haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,        —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇,        —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇,        —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇,        —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁,        —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,        —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —NR₇C(S)R₇,        —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,        —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR)NR₁₀R₁₁, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,        —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁,        —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇,        —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;    -   R₂ is —H, —OH, —SH, —NR₇H, —OR₁₅, —SR₁₅, —NHR₁₅, —O(CH₂)_(m)OH,        —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,        —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,        —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,        —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇,        —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁,        —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,        —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,        —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇,        —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇,        —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,        —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,        —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,        —SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁;    -   R³ is —H, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a        haloalkyl, a heteroalkyl, —C(O)R⁷, —(CH₂)_(m)C(O)OR₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —S(O)_(p)R₇, —S(O)_(p)OR₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R⁴ is —H, —OH, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo,        cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, —C(O)R₇,        —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇,        —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁, or        R₃ and R₄ taken together with the carbon atoms to which they are        attached form an optionally substituted cycloalkenyl, an        optionally substituted aryl, an optionally substituted        heterocyclyl, or an optionally substituted heteroaryl;    -   R₇ and R₈, for each occurrence, are, independently, —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₀ and R₁₁, for each occurrence, are independently —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₀ and R₁₁, taken together with the nitrogen to which they        are attached, form an optionally substituted heterocyclyl or an        optionally substituted heteroaryl;    -   R₁₅, for each occurrence, is independently, a lower alkyl;    -   p, for each occurrence, is, independently, 1 or 2; and    -   m, for each occurrence, is independently, 1, 2, 3, or 4.

In an embodiment, in formula (I) or (Ia), X is CR₄. In anotherembodiment, in formula (I) or (Ia), X is N.

In another embodiment, in formula (I) or (Ia), R₁ may be —H, loweralkyl, lower alkoxy, lower cycloalkyl, or lower cycloalkoxy.

In another embodiment, in formula (I) or (Ia), R₁ may be —H, methyl,ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, orcyclopropoxy.

In another embodiment, in formula (I) or (Ia), R³ may be —H, a loweralkyl, a lower cycloalkyl, —C(O)N(R₂₇)₂, or —C(O)OH, wherein R₂₇ is —Hor a lower alkyl.

In another embodiment, in formula (I) or (Ia), R₃ may be —H, methyl,ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, —C(O)OH, —(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, or—C(O)N(CH₃)₂.

In another embodiment, R₄ may be H or a lower alkyl. In anotherembodiment, in formula (I) or (Ia), R₄ may be —H, methyl, ethyl, propyl,isopropyl or cyclopropyl.

In another embodiment, in formula (I) or (Ia), R₁ may be —H, —OH, —SH,—NH₂, a lower alkoxy or a lower alkyl amino. In another embodiment, informula (I) or (Ia), R₁ may be —H, —OH, methoxy or ethoxy.

In another embodiment, in formula (I) or (Ia), Z is —OH.

In another embodiment, in formula (I) or (Ia), Z is —SH.

In another embodiment, in formula (I) or (Ia), R₂ may be —H, —OH, —SH,—NH₂, a lower alkoxy or a lower alkyl amino.

In another embodiment, in formula (I) or (Ia), R₂ may be —H, —OH,methoxy, or ethoxy.

In another embodiment, in formula (I) or (Ia), R₁ may be —H, methyl,ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, orcyclopropoxy; R₃ may be —H, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, or —C(O)N(CH₃)₂; R₄ may be —H,methyl, ethyl, propyl, isopropyl or cyclopropyl; R₂ may be —H, —OH, —SH,—NH₂, a lower alkoxy or a lower alkyl amino; and Z is OH.

In another embodiment, in formula (I) or (Ia), R₁ may be —H, methyl,ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, orcyclopropoxy; R₃ may be of —H, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, or —C(O)N(CH₃)₂; R₄ may be —H,methyl, ethyl, propyl, isopropyl or cyclopropyl; R₂ may be of —H, —OH,—SH, —NH₂, a lower alkoxy or a lower alkyl amino; and Z is SH.

In another embodiment, the compound may be:

-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-hydroxy-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxyphenyl)-4-(1-methoxyethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxyphenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-butyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-hexyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1-methylcyclopropyl)-indol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-isopropyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,    or-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,    or a tautomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound may be:

-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole    HCL salt,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,-   3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-2-methyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,    or-   3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-2-trifluoromethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,    or a tautomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound may be:

-   5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl    dihydrogen phosphate,-   sodium    5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl    phosphate,-   2-(3,4-dimethoxyphenethyl)-5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)phenyl    dihydrogen phosphate,-   5-hydroxy-2-isopropyl-4-(5-mercapto-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)phenyl    dihydrogen phosphate,-   5-hydroxy-4-(5-hydroxy-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl    dihydrogen phosphate, or-   4-(4-(1,3-dimethyl-1H-indol-5-yl)-5-hydroxy-4H-1,2,4-triazol-3-yl)-2-ethyl-5-hydroxyphenyl    dihydrogen phosphate,

or a tautomer, or a pharmaceutically acceptable salt thereof.

Hsp90 inhibitory compounds, as well as tautomers or pharmaceuticallyacceptable salts thereof that may be used in the methods describedherein are depicted in Tables 1 or 2.

TABLE 1 STRUCTURE TAUTOMERIC STRUCTURE NAME  1

3-(2,4-DIHYDROXY-5- ISOPROPYL-PHENYL)-4-(1- METHYL-INDOL-5-YL)-5-HYDROXY-[1,2,4] TRIAZOLE (GANETESPIB)  2

3-(2,4- DIHYDROXYPHENYL)-4- (1-ETHYL-INDOL-4-YL)-5- MERCAPTO-[1,2,4]TRIAZOLE  3

3-(2,4-DIHYDROXY- PHENYL)-4- (2,3-DIMETHYL- 1H-INDOL-4-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE  4

3-(2,4- DIHYDROXYPHENYL)-4- (1-ISOPROPYL- INDOL-4-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE  5

3-(2,4-DIHYDROXY- PHENYL)-4- (INDOL-4-YL)-5- MERCAPTO- [1,2,4] TRIAZOLE 6

3-(2,4-DIHYDROXY- PHENYL)-4- [1-(2-METHOXYETHOXY)- INDOL-4-YL]-5-MERCAPTO- [1,2,4] TRIAZOLE  7

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1- ISOPROPYL- INDOL-4-YL)-5-MERCAPTO- [1,2,4] TRIAZOLE  8

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-[1- (DIMETHYL- CARBAMOYL)-INDOL-4-YL]-5- MERCAPTO-[1,2,4] TRIAZOLE  9

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-ETHYL- BENZOIMIDAZOL-4-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 10

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1,2,3- TRIMETHYL- INDOL-5-YL)-5-MERCAPTO- [1,2,4] TRIAZOLE 11

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-ISOPROPYL-INDOL-3-YL)-5-HYDROXY- [1,2,4] TRIAZOLE 12

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4- (1-ISOPROPYL- INDOL-4-YL)-5-AMINO-[1,2,4] TRIAZOLE 15

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1- ISOPROPYL- INDOL-4-YL)-5-UREIDO-[1,2,4] TRIAZOLE 16

3-(2,4-DIHYDROXY-5- ETHYL- PHENYL)-4-(1- METHYL-INDOL- 4-YL)-5-CARBAMOYLOXY- [1,2,4] TRIAZOLE 17

3-(2,4-DIHYDROXY- PHENYL)-4- (1-METHYL-2- CHLORO-INDOL- 4-YL)-5-CARBAMOYLOXY- [1,2,4] TRIAZOLE 18

3-(2,4-DIHYDROXY-5- METHOXY-PHENYL)-4-(1- ISOPROPYL- BENZOIMIDAZOL-4-YL)-5- (SULFAMOYLAMINO)- [1,2,4] TRIAZOLE 20

3-(2,4-DIHYDROXY-5- METHOXY-PHENYL)-4-(1- ISOPROPYL- BENZOIMIDAZOL-4-YL)-5- (SULFAMOYLOXY)- [1,2,4] TRIAZOLE 21

3-(2-HYDROXY-4- ETHOXYCARBONYOXY-5- METHOXY-PHENYL)-4-(1- ISOPROPYL-BENZOIMIDAZOL- 4-YL)-5-HYDROXY-[1,2,4] TRIAZOLE 22

3-[2-HYDROXY-4- ISOBUTYRYLOXY- 5-ETHYL- PHENYL]-4- (1-METHYL-BENZO-IMIDAZOL-4-YL)-5- HYDROXY- [1,2,4] TRIAZOLE 23

3-(2,4-DIHYDROXY- PHENYL)-4- (1-DIMETHYL- CARBAMOYL- INDOL-4-YL)-5-MERCAPTO- [1,2,4] TRIAZOLE 24

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(2,3- DIMETHYL- INDOL-5-YL)-5-MERCAPTO- [1,2,4] TRIAZOLE 25

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-ETHYL-1H- BENZOIMIDAZOL-4-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE, HCL SALT 26

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1- ISOPROPYL-7- METHOXY-INDOL-4-YL)-5- MERCAPTO-[1,2,4] TRIAZOLE 27

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1- PROPYL-INDOL-4-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 28

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-ACETYL-2,3- DIMETHYL-INDOL-5-YL)-5- MERCAPTO-[1,2,4] TRIAZOLE 29

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(2-METHYL-3- ETHYL-BENZIMIDAZOL-5-YL)- 5-MERCAPTO-[1,2,4] TRIAZOLE 30

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-ETHYL-2- METHYL-BENZIMIDAZOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 31

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-PROPYL-2,3- DIMETHYL-INDOL-5-YL)-5- MERCAPTO-[1,2,4] TRIAZOLE 34

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-N- BUTYL-INDOL-4-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 35

3-(2,4-DIHYDROXY-5- ETHYL- PHENYL)-4-(1-N-PENTYL- INDOL-4-YL)-5-MERCAPTO- [1,2,4] TRIAZOLE 36

3-(2,4-DIHYDROXY-5- ETHYL- PHENYL)-4-(1-N- HEXYL-INDOL-4-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 37

3-(2,4-DIHYDROXY-5- CYCLOPROPYL- PHENYL)-4-(1- (1-METHYL- CYCLOPROPYL)-INDOL-4-YL)-5- MERCAPTO- [1,2,4] TRIAZOLE 38

3-(2,4-DIHYDROXY-5- CYCLOPROPYL- PHENYL)-4-(1- ISOPROPYL-7-METHOXY-INDOL-4-YL)-5-MERCAPTO- [1,2,4] TRIAZOLE 39

3-(2,4-DIHYDROXY-5- CYCLOPROPYL- PHENYL)-4- (1,2,3-TRIMETHYL- INDOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 40

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1- ISOPROPYL-7-METHOXY-INDOL-4-YL)- 5-MERCAPTO-[1,2,4] TRIAZOLE DISODIUM SALT 41

3-(2,4-DIHYDROXY- 5-TERT- BUTYL-PHENYL)-4-(1- ISOPROPYL-7-METHOXY-INDOL-4-YL)-5- MERCAPTO- [1,2,4] TRIAZOLE 42

3-(2,4-DIHYDROXY-5- CYCLOPROPYL-PHENYL)- 4-(1-PROPYL-7- METHOXY-INDOL-4-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 43

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-METHYL-3- ETHYL-INDOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 44

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1,3- DIMETHYL- INDOL-5-YL)-5-MERCAPTO- [1,2,4] TRIAZOLE 45

3-(2,4-DIHYDROXY-5- ISOPROPYL-PHENYL)-4-(1- ISOPROPYL-7-METHOXY-INDOL-4-YL)-5- MERCAPTO- [1,2,4] TRIAZOLE 46

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1-METHYL-3- ISOPROPYL-INDOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 48

3-(2,4-DIHYDROXY- 5-ETHYL-PHENYL)-4- (1-ISOPROPYL-7- HYDROXY-INDOL-4-YL)-5- MERCAPTO-[1,2,4] TRIAZOLE 49

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1- ISOPROPYL-7-ETHOXY-INDOL-4-YL)-5- MERCAPTO-[1,2,4] TRIAZOLE 50

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1,2- DIMETHYL- INDOL-5-YL)-5-MERCAPTO- [1,2,4] TRIAZOLE 51

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(N-METHYL- INDOL-5-YL)-5- MERCAPTO-[1,2,4] TRIAZOLE 55

3-(2,4-DIHYDROXY-5- ISOPROPYL-PHENYL)-4- (1,3-DIMETHYL-INDOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 56

3-(2,4-DIHYDROXY-5- CYCLOPROPYL- PHENYL)-4-(1,3- DIMETHYL-INDOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 57

3-(2,4-DIHYDROXY- 5-ETHYL- PHENYL)-4-(1,3- DIMETHYL-INDOL-5-YL)-5-HYDROXY- [1,2,4] TRIAZOLE 58

3-(2,4-DIHYDROXY-5- ISOPROPYL-PHENYL)-4-(N- METHYL-INDOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 59

3-(2,4-DIHYDROXY-5- ISOPROPYL-PHENYL)-4- (1,2-DIMETHYL-INDOL- 5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 60

3-(2,4-DIHYDROXY-5- ISOPROPYL- PHENYL)-4-(1,3- DIMETHYL- INDOL-5-YL)-5-HYDROXY-[1,2,4] TRIAZOLE 62

3-(2,4-DIHYDROXY-5- ISOPROPYL- PHENYL)-4-(1H- INDOL-5-YL)-5- MERCAPTO-[1,2,4] TRIAZOLE 63

3-(2,4-DIHYDROXY-5- ISOPROPYL- PHENYL)-4-(1- ETHYL-INDOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 64

3-(2,4-DIHYDROXY-5- ISOPROPYL-PHENYL)-4-(1- PROPYL-INDOL-5-YL)-5-MERCAPTO-[1,2,4] TRIAZOLE 65

3-(2,4-DIHYDROXY-5- ISOPROPYL- PHENYL)-4-(1- METHYL-2- TRIFLUOROMETHYL-BENZIMIDAZOL-5-YL)-5- MERCAPTO-[1,2,4] TRIAZOLE 66

3-(2,4-DIHYDROXY-5- ISOPROPYL-PHENYL)-4- (1-ISOPROPYL-INDOL- 4-YL)-5-HYDROXY-[1,2,4] TRIAZOLE

TABLE 2 Compounds according to Formula (Ia) NO. STRUCTURE TAUTOMERICSTRUCTURE NAME 1A

5-HYDROXY-4-(5- HYDROXY-4-(1- METHYL-1H-INDOL- 5-YL)-4H-1,2,4-TRIAZOL-3-YL)-2- ISOPROPYLPHENYL DIHYDROGEN PHOSPHATE 2A

SODIUM 5-HYDROXY-4- (5-HYDROXY-4-(1- METHYL-1H-INDOL-5-YL)-4H-1,2,4-TRIAZOL- 3-YL)-2- ISOPROPYLPHENYL PHOSPHATE 3A

2-(3,4- DIMETHOXY- PHENETHYL)- 5-HYDROXY-4-(5- HYDROXY-4-(1-METHYL-1H-INDOL-5- YL)-4H-1,2,4-TRIAZOL- 3-YL)PHENYL DIHYDROGENPHOSPHATE 4A

4-(4-(1,3-DIMETHYL- 1H-INDOL-5-YL)-5- HYDROXY-4H-1,2,4- TRIAZOL-3-YL)-2-ETHYL-5- HYDROXYPHENYL DIHYDROGEN PHOSPHATE

The Hsp90 inhibitory compounds used in the disclosed combination methodscan be prepared according to the procedures disclosed in U.S. PatentPublication No. 2006/0,167,070, and WO2009/023,211.

These triazolone compounds typically can form a tautomeric structure asshown below and as exemplified by the tautomeric structures shown inTables 1 and 2:

In an embodiment, the present invention provides a pharmaceuticalcombination for the treatment, prophylaxis, and amelioration ofproliferative disorders, such as cancer. In a specific embodiment, thecombination comprises one or more Hsp90 inhibitors according to formulae(I) or (Ia), or a compound in Tables 1 or 2, or a tautomer or apharmaceutically acceptable salt thereof in addition to aplatinum-containing anti-cancer agent.

In an embodiment, the combination includes a pharmaceutical compositionor a single unit dosage form containing both an Hsp90 inhibitor and aplatinum-containing anti-cancer agent. Pharmaceutical combinations anddosage forms described herein comprise the two active ingredients inrelative amounts and formulated in such a way that a givenpharmaceutical combination or dosage form can be used to treatproliferative disorders, such as cancer. Preferred pharmaceuticalcombinations and dosage forms comprise a compound of formulae (I) or(Ia), or a compound in Tables 1 or 2, or a tautomer or pharmaceuticallyacceptable salt thereof, in combination with a platinum-containinganticancer agent. In other embodiments, the Hsp90 inhibitor and theplatinum-containing anticancer agent may be in individual or separatepharmaceutical compositions, depending on the dosing schedules,preferred routes of administration, and available formulations of thetwo compounds. Optionally, these embodiments can also contain one ormore additional therapeutic agents.

The pharmaceutical combinations described herein are formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral, intranasal (e.g., inhalation), transdermal(topical), transmucosal, and rectal administration. In a specificembodiment, the combination is formulated in accordance with routineprocedures as a pharmaceutical composition adapted for intravenous,subcutaneous, intramuscular, oral, intranasal or topical administrationto human beings. In an embodiment, the combination is formulated inaccordance with routine procedures for subcutaneous administration tohuman beings.

In a specific embodiment, the combination therapies described hereincomprise one or more compounds and at least one other therapy which hasthe same mechanism of action as the compounds. In another specificembodiment, the combination therapies described herein comprise one ormore compounds described herein and at least one other therapy which hasa different mechanism of action than the compounds. In certainembodiments, the combination therapies described herein improve thetherapeutic effect of one or more triazolone compounds described hereinby functioning together with the platinum-containing anticancer agent tohave an additive or synergistic effect. In certain embodiments, thecombination therapies described herein reduce the side effectsassociated with the therapies. In certain embodiments, the combinationtherapies described herein reduce the effective dosage of one or more ofthe therapies.

In a specific embodiment, the combination comprising one or moretriazolone compounds described herein is administered to a subject,preferably a human, to prevent, treat, manage, or ameliorate cancer, orone or more symptom thereof. In accordance with the invention, thepharmaceutical combinations described herein may also comprise one ormore other agents being used, have been used, or are known to be usefulin the treatment or amelioration of cancer, particularly breast cancer,gastric cancer, colorectal cancer, pancreatic cancer, ocular melanoma,prostate cancer, gastrointestinal stromal tumors (GIST), advancedesophagogastric cancer, melanoma, hepatocellular cancer, solid tumor,liver cancer, head and neck cancer, small cell lung cancer, non-smallcell lung cancer, bladder cancer, or colon cancer. The pharmaceuticalcombinations described herein utilize pharmaceutical compositions anddosage forms which comprise one or more excipients. Suitable excipientsare well known to those skilled in the art of pharmacy.

The triazolone compounds described herein can be also formulated into oradministered by controlled release means or by delivery devices that arewell known to those of ordinary skill in the art. Examples include thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;and U.S. Pat. Nos. 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566.

In an embodiment, the present invention also provides a method oftreating a proliferative disorder in a subject, comprising administeringto the subject an effective amount of the combination of an Hsp90inhibitor and a platinum-containing anticancer agent as describedherein. In an embodiment, the proliferative disorder is cancer. In oneaspect of this embodiment, the cancer is breast cancer, gastric cancer,colorectal cancer, pancreatic cancer, ocular melanoma, prostate cancer,gastrointestinal stromal tumors (GIST), advanced esophagogastric cancer,melanoma, hepatocellular cancer, solid tumor, liver cancer, head andneck cancer, small cell lung cancer, non-small cell lung cancer, bladdercancer, testicular tumor, ovarian cancer, lymphoma, leukemia, multiplemyeloma, or colon cancer.

Other anti-proliferative or anti-cancer therapies may be combined withthe compounds described herein to treat proliferative diseases andcancer. Other therapies or anti-cancer agents that may be used incombination with the inventive anti-cancer agents described hereininclude surgery, radiotherapy (including gamma-radiation, neutron beamradiotherapy, electron beam radiotherapy, proton therapy, brachytherapy,and systemic radioactive isotopes), endocrine therapy, biologic responsemodifiers (including interferons, interleukins, and tumor necrosisfactor (TNF)), hyperthermia and cryotherapy, agents to attenuate anyadverse effects (e.g., antiemetics), and other approved chemotherapeuticdrugs.

The therapeutic agents of the combination therapies described herein canbe administered sequentially or concurrently. In an embodiment, theadministration of the Hsp90 inhibitor and the platinum-containinganticancer agent are done concurrently. In another embodiment, theadministration of the Hsp90 inhibitor and the platinum-containinganticancer agent are done separately. In another embodiment, theadministration of the Hsp90 inhibitor and the platinum-containinganticancer agent are done sequentially. In an embodiment, theadministration of the Hsp90 inhibitor and the platinum-containinganticancer agent are done until the cancer is cured or stabilized orimproved.

In a specific embodiment, the present method includes treating,managing, or ameliorating cancer, or one or more symptoms thereof,comprising administering to a subject in need thereof one or morecompounds represented by the structural formulae (I) or (Ia) or acompound in Table 1 or Table 2, in combination with aplatinum-containing anticancer agent such as cisplatin, carboplatin, oroxaliplatin, wherein the cancer is breast cancer, gastric cancer,colorectal cancer, pancreatic cancer, ocular melanoma, prostate cancer,gastrointestinal stromal tumors (GIST), advanced esophagogastric cancer,melanoma, hepatocellular cancer, solid tumor, liver cancer, head andneck cancer, small cell lung cancer, non-small cell lung cancer, bladdercancer, testicular tumor, ovarian cancer, lymphoma, leukemia, multiplemyeloma, or colon cancer.

In another embodiment, the method of treating a subject with cancerincludes administering to the subject an effective amount of atriazolone compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with an effective amount of a platinum-containing anticanceragent such as cisplatin, carboplatin, or oxaliplatin. In an embodiment,the cancer has a KRAS mutation. In an embodiment, the cancer has an ALKmutation. In an embodiment, the cancer has a BRAF mutation.

In another embodiment, the method of treating a subject with cancerincludes administering to the subject an effective amount of atriazolone compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with an effective amount of cisplatin. In anotherembodiment, the method of treating a subject with cancer includesadministering to the subject an effective amount of a triazolonecompound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with a synergistic amount of cisplatin. In an embodiment,cisplatin is administered IV at a dose of between about 20 mg/m² toabout 150 mg/m². In an embodiment, cisplatin is administered at a doseof about 20 mg/m² once daily. In an embodiment, cisplatin isadministered IV at about 20 mg/m² once daily for 5 days per cycle. In anembodiment, cisplatin is administered IV at a dose of between about 75mg/m² to about 100 mg/m². In an embodiment, cisplatin is administered IVat a dose of between about 75 mg/m² to about 100 mg/m² once every 4weeks per cycle. In an embodiment, cisplatin is administered IV at adose of about 100 mg/m² once every 4 weeks per cycle. In an embodiment,cisplatin is administered IV at a dose of between about 50 mg/m² toabout 70 mg/m² once every 3 or 4 weeks per cycle. In an embodiment, theamount of the Hsp90 inhibitor is from about 2 mg/m² to about 260 mg/m².In an embodiment, the amount of the Hsp90 inhibitor is about 75 mg/m²,about 85 mg/m², about 100 mg/m², about 110 mg/m², about 115 mg/m², about120 mg/m², about 145 mg/m², about 150 mg/m², about 175 mg/m², about 180mg/m², about 200 mg/m², about 215 mg/m² or about 260 mg/m². In anembodiment, the Hsp90 inhibitor is administered IV once weekly or twiceweekly. In any one of the above embodiments, the cancer may have a KRASmutation. In any one of the above embodiments, the cancer may have anALK mutation. In any one of the above embodiments, the cancer may have aBRAF mutation.

In another embodiment, the method of treating a subject with cancerincludes administering to the subject an effective amount of atriazolone compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with an effective amount of aplatinum-containing anticancer agent such as cisplatin, carboplatin, oroxaliplatin. In an embodiment, the cancer has a KRAS mutation. In anembodiment, the cancer has an ALK mutation. In an embodiment, the cancerhas a BRAF mutation.

In another embodiment, the method of treating a subject with cancerincludes administering to the subject an effective amount of atriazolone compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with an effective amount of cisplatin. Inanother embodiment, the method of treating a subject with cancerincludes administering to the subject an effective amount of atriazolone compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with a synergistic amount of cisplatin. Inan embodiment, cisplatin is administered IV at a dose of between about20 mg/m² to about 150 mg/m². In an embodiment, cisplatin is administeredat a dose of about 20 mg/m² once daily. In an embodiment, cisplatin isadministered IV at about 20 mg/m² once daily for 5 days per cycle. In anembodiment, cisplatin is administered IV at a dose of between about 75mg/m² to about 100 mg/m². In an embodiment, cisplatin is administered IVat a dose of between about 75 mg/m² to about 100 mg/m² once every 4weeks per cycle. In an embodiment, cisplatin is administered IV at adose of about 100 mg/m² once every 4 weeks per cycle. In an embodiment,cisplatin is administered IV at a dose of between about 50 mg/m² toabout 70 mg/m² once every 3 or 4 weeks per cycle. In an embodiment, theamount of the Hsp90 inhibitor is from about 2 mg/m² to about 260 mg/m².In an embodiment, the amount of the Hsp90 inhibitor is about 75 mg/m²,about 85 mg/m², about 100 mg/m², about 110 mg/m², about 115 mg/m², about120 mg/m², about 145 mg/m², about 150 mg/m², about 175 mg/m², about 180mg/m², about 200 mg/m², about 215 mg/m² or about 260 mg/m². In anembodiment, the Hsp90 inhibitor is administered IV once weekly or twiceweekly. In any one of the above embodiments, the cancer may have a KRASmutation. In any one of the above embodiments, the cancer may have anALK mutation. In any one of the above embodiments, the cancer may have aBRAF mutation.

In another embodiment, the method of treating a subject with cancerincludes administering to the subject an effective amount of atriazolone compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with a platinum-containing anticancer agent such ascisplatin, carboplatin, or oxaliplatin, wherein the cancer is breastcancer, gastric cancer, colorectal cancer, pancreatic cancer, ocularmelanoma, prostate cancer, gastrointestinal stromal tumors (GIST),advanced esophagogastric cancer, melanoma, hepatocellular cancer, solidtumor, liver cancer, head and neck cancer, small cell lung cancer,non-small cell lung cancer, bladder cancer, testicular tumor, ovariancancer, lymphoma, leukemia, multiple myeloma, or colon cancer. In anembodiment, the cancer has a KRAS mutation. In an embodiment, the cancerhas an ALK mutation. In an embodiment, the cancer has a BRAF mutation.

In another embodiment, the method of treating a subject with cancerincludes administering to the subject an effective amount of atriazolone compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with a platinum-containing anticancer agentsuch as cisplatin, carboplatin, or oxaliplatin, wherein the cancer isbreast cancer, gastric cancer, colorectal cancer, pancreatic cancer,ocular melanoma, prostate cancer, gastrointestinal stromal tumors(GIST), advanced esophagogastric cancer, melanoma, hepatocellularcancer, solid tumor, liver cancer, head and neck cancer, small cell lungcancer, non-small cell lung cancer, bladder cancer, testicular tumor,ovarian cancer, lymphoma, leukemia, multiple myeloma, or cancer. In anembodiment, the cancer has a KRAS mutation. In an embodiment, the cancerhas an ALK mutation. In an embodiment, the cancer has a BRAF mutation.

In yet another embodiment, the method of treating a subject with cancer,wherein the subject is being or has been treated with a chemotherapeuticagent, includes administering to the subject an effective amount of atriazolone compound represented by the structural formulae (I) or (Ia)or a compound in Table 1 or Table 2, in combination with aplatinum-containing anticancer agent such as cisplatin, carboplatin, oroxaliplatin. In an embodiment, the cancer has a KRAS mutation. In anembodiment, the cancer has an ALK mutation. In an embodiment, the cancerhas a BRAF mutation.

In an embodiment, the method of treating a subject with cancer, whereinthe subject is being or has been treated with a chemotherapeutic agent,includes administering to the subject an effective amount of atriazolone compound represented by the structural formulae (I) or (Ia)or a compound in Table 1 or Table 2, in combination with aplatinum-containing anticancer agent such as cisplatin, carboplatin, oroxaliplatin, wherein the cancer is breast cancer, gastric cancer,colorectal cancer, pancreatic cancer, ocular melanoma, prostate cancer,gastrointestinal stromal tumors (GIST), advanced esophagogastric cancer,melanoma, hepatocellular cancer, solid tumor, liver cancer, head andneck cancer, small cell lung cancer, non-small cell lung cancer, bladdercancer, testicular tumor, ovarian cancer, lymphoma, leukemia, multiplemyeloma, or colon cancer. In an embodiment, the cancer has a KRASmutation. In an embodiment, the cancer has an ALK mutation. In anembodiment, the cancer has a BRAF mutation.

In another embodiment, the method of treating a subject with cancer,wherein the subject is being or has been treated with a chemotherapeuticagent, includes administering to the subject an effective amount of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with a platinum-containing anticancer agent such ascisplatin, carboplatin, or oxaliplatin. In an embodiment, the cancer hasa KRAS mutation. In an embodiment, the cancer has an ALK mutation. In anembodiment, the cancer has a BRAF mutation.

In another embodiment, the method of treating a subject with cancer,wherein the subject is being or has been treated with a chemotherapeuticagent, includes administering to the subject an effective amount of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with cisplatin. In an embodiment, cisplatin is administeredIV at a dose of between about 20 mg/m² to about 150 mg/m². In anembodiment, cisplatin is administered at a dose of about 20 mg/m² oncedaily. In an embodiment, cisplatin is administered IV at about 20 mg/m²once daily for 5 days per cycle. In an embodiment, cisplatin isadministered IV at a dose of between about 75 mg/m² to about 100 mg/m².In an embodiment, cisplatin is administered IV at a dose of betweenabout 75 mg/m² to about 100 mg/m² once every 4 weeks per cycle. In anembodiment, cisplatin is administered IV at a dose of about 100 mg/m²once every 4 weeks per cycle. In an embodiment, cisplatin isadministered IV at a dose of between about 50 mg/m² to about 70 mg/m²once every 3 or 4 weeks per cycle. In an embodiment, the amount of theHsp90 inhibitor is from about 2 mg/m² to about 260 mg/m². In anembodiment, the amount of the Hsp90 inhibitor is about 75 mg/m², about85 mg/m², about 100 mg/m², about 110 mg/m², about 115 mg/m², about 120mg/m², about 145 mg/m², about 150 mg/m², about 175 mg/m², about 180mg/m², about 200 mg/m², about 215 mg/m² or about 260 mg/m². In anembodiment, the Hsp90 inhibitor is administered IV once weekly or twiceweekly. In any one of the above embodiments, the cancer may have a KRASmutation. In any one of the above embodiments, the cancer may have anALK mutation. In any one of the above embodiments, the cancer may have aBRAF mutation.

In another embodiment, the method of treating a subject with cancer,wherein the subject is being or has been treated with a chemotherapeuticagent, includes administering to the subject an effective amount of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with a platinum-containing anticancer agentsuch as cisplatin, carboplatin, or oxaliplatin. In an embodiment, thecancer has a KRAS mutation. In an embodiment, the cancer has an ALKmutation. In an embodiment, the cancer has a BRAF mutation.

In another embodiment, the method of treating a subject with cancer,wherein the subject is being or has been treated with a chemotherapeuticagent, includes administering to the subject an effective amount of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with cisplatin. In an embodiment, cisplatinis administered IV at a dose of between about 20 mg/m² to about 150mg/m². In an embodiment, cisplatin is administered at a dose of about 20mg/m² once daily. In an embodiment, cisplatin is administered IV atabout 20 mg/m² once daily for 5 days per cycle. In an embodiment,cisplatin is administered IV at a dose of between about 75 mg/m² toabout 100 mg/m². In an embodiment, cisplatin is administered IV at adose of between about 75 mg/m² to about 100 mg/m² once every 4 weeks percycle. In an embodiment, cisplatin is administered IV at a dose of about100 mg/m² once every 4 weeks per cycle. In an embodiment, cisplatin isadministered IV at a dose of between about 50 mg/m² to about 70 mg/m²once every 3 or 4 weeks per cycle. In an embodiment, the amount of theHsp90 inhibitor is from about 2 mg/m² to about 260 mg/m². In anembodiment, the amount of the Hsp90 inhibitor is about 75 mg/m², about85 mg/m², about 100 mg/m², about 110 mg/m², about 115 mg/m², about 120mg/m², about 145 mg/m², about 150 mg/m², about 175 mg/m², about 180mg/m², about 200 mg/m², about 215 mg/m² or about 260 mg/m². In anembodiment, the Hsp90 inhibitor is administered IV once weekly or twiceweekly. In any one of the above embodiments, the cancer may have a KRASmutation. In any one of the above embodiments, the cancer may have anALK mutation. In any one of the above embodiments, the cancer may have aBRAF mutation.

In an embodiment, the method of treating a subject with cancer, whereinthe subject is being or has been treated with a chemotherapeutic agent,includes administering to the subject an effective amount of atriazolone compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with a platinum-containing anticancer agent such ascisplatin, carboplatin, or oxaliplatin, wherein the cancer is breastcancer, gastric cancer, colorectal cancer, pancreatic cancer, ocularmelanoma, prostate cancer, gastrointestinal stromal tumors (GIST),advanced esophagogastric cancer, melanoma, hepatocellular cancer, solidtumor, liver cancer, head and neck cancer, small cell lung cancer,non-small cell lung cancer, bladder cancer, testicular tumor, ovariancancer, lymphoma, leukemia, multiple myeloma, or colon cancer. In anembodiment, the cancer has a KRAS mutation. In an embodiment, the cancerhas an ALK mutation. In an embodiment, the cancer has a BRAF mutation.

In an embodiment, the method of treating a subject with cancer, whereinthe subject is being or has been treated with a chemotherapeutic agent,includes administering to the subject an effective amount of atriazolone compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with a platinum-containing anticancer agentsuch as cisplatin, carboplatin, or oxaliplatin, wherein the cancer isbreast cancer, gastric cancer, colorectal cancer, pancreatic cancer,ocular melanoma, prostate cancer, gastrointestinal stromal tumors(GIST), advanced esophagogastric cancer, melanoma, hepatocellularcancer, solid tumor, liver cancer, head and neck cancer, small cell lungcancer, non-small cell lung cancer, bladder cancer, testicular tumor,ovarian cancer, lymphoma, leukemia, multiple myeloma, or colon cancer.In an embodiment, the cancer has a KRAS mutation. In an embodiment, thecancer has an ALK mutation. In an embodiment, the cancer has a BRAFmutation.

In an embodiment, the method of treating a subject with cancer, whereinthe subject has proven refractory to other therapies but is no longer onthese therapies, includes administering to the subject an effectiveamount of a triazolone compound represented by the structural formulae(I) or (Ia) or a compound in Table 1 or Table 2, in combination with aplatinum-containing anticancer agent such as cisplatin, carboplatin, oroxaliplatin, wherein the cancer is breast cancer, gastric cancer,colorectal cancer, pancreatic cancer, ocular melanoma, prostate cancer,gastrointestinal stromal tumors (GIST), advanced esophagogastric cancer,melanoma, hepatocellular cancer, solid tumor, liver cancer, head andneck cancer, small cell lung cancer, non-small cell lung cancer, bladdercancer, testicular tumor, ovarian cancer, lymphoma, leukemia, multiplemyeloma, or colon cancer. In an embodiment, the cancer has a KRASmutation. In an embodiment, the cancer has an ALK mutation. In anembodiment, the cancer has a BRAF mutation.

In another embodiment, the method of treating a subject with cancer,wherein the subject has proven refractory to other therapies but is nolonger on these therapies, includes administering to the subject aneffective amount of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with a platinum-containing anticancer agent such ascisplatin, carboplatin, or oxaliplatin. In an embodiment, the cancer hasa KRAS mutation. In an embodiment, the cancer has an ALK mutation. In anembodiment, the cancer has a BRAF mutation.

In another embodiment, the method of treating a subject with cancer,wherein the subject has proven refractory to other therapies but is nolonger on these therapies, includes administering to the subject aneffective amount of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with cisplatin. In an embodiment, cisplatin is administeredIV at a dose of between about 20 mg/m² to about 150 mg/m². In anembodiment, cisplatin is administered at a dose of about 20 mg/m² oncedaily. In an embodiment, cisplatin is administered IV at about 20 mg/m²once daily for 5 days per cycle. In an embodiment, cisplatin isadministered IV at a dose from about 75 mg/m² to about 100 mg/m². In anembodiment, cisplatin is administered IV at a dose from about 75 mg/m²to about 100 mg/m² once every 4 weeks per cycle. In an embodiment,cisplatin is administered IV at a dose of about 100 mg/m² once every 4weeks per cycle. In an embodiment, cisplatin is administered IV at adose of between about 50 mg/m² to about 70 mg/m² once every 3 or 4 weeksper cycle. In an embodiment, the amount of the Hsp90 inhibitor is fromabout 2 mg/m² to about 260 mg/m². In an embodiment, the amount of theHsp90 inhibitor is about 75 mg/m², about 85 mg/m², about 100 mg/m²,about 110 mg/m², about 115 mg/m², about 120 mg/m², about 145 mg/m²,about 150 mg/m², about 175 mg/m², about 180 mg/m², about 200 mg/m²,about 215 mg/m² or about 260 mg/m². In an embodiment, the Hsp90inhibitor is administered IV once weekly or twice weekly. In any one ofthe above embodiments, the cancer may have a KRAS mutation. In any oneof the above embodiments, the cancer may have an ALK mutation. In anyone of the above embodiments, the cancer may have a BRAF mutation.

In another embodiment, the method of treating a subject with cancer,wherein the subject has proven refractory to other therapies but is nolonger on these therapies, includes administering to the subject aneffective amount of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with a platinum-containing anticancer agentsuch as cisplatin, carboplatin, or oxaliplatin. In an embodiment, thecancer has a KRAS mutation. In an embodiment, the cancer has an ALKmutation. In an embodiment, the cancer has a BRAF mutation.

In another embodiment, the method of treating a subject with cancer,wherein the subject has proven refractory to other therapies but is nolonger on these therapies, includes administering to the subject aneffective amount of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with cisplatin. In an embodiment, cisplatinis administered IV at a dose of between about 20 mg/m² to about 150mg/m². In an embodiment, cisplatin is administered at a dose of about 20mg/m² once daily. In an embodiment, cisplatin is administered IV atabout 20 mg/m² once daily for 5 days per cycle. In an embodiment,cisplatin is administered IV at a dose from about 75 mg/m² to about 100mg/m². In an embodiment, cisplatin is administered IV at a dose fromabout 75 mg/m² to about 100 mg/m² once every 4 weeks per cycle. In anembodiment, cisplatin is administered IV at a dose of about 100 mg/m²once every 4 weeks per cycle. In an embodiment, cisplatin isadministered IV at a dose from about 50 mg/m² to about 70 mg/m² onceevery 3 or 4 weeks per cycle. In an embodiment, the amount of the Hsp90inhibitor is from about 2 mg/m² to about 260 mg/m². In an embodiment,the amount of the Hsp90 inhibitor is about 75 mg/m², about 85 mg/m²,about 100 mg/m², about 110 mg/m², about 115 mg/m², about 120 mg/m²,about 145 mg/m², about 150 mg/m², about 175 mg/m², about 180 mg/m²,about 200 mg/m², about 215 mg/m² or about 260 mg/m². In an embodiment,the Hsp90 inhibitor is administered IV once weekly or twice weekly. Inany one of the above embodiments, the cancer may have a KRAS mutation.In any one of the above embodiments, the cancer may have an ALKmutation. In any one of the above embodiments, the cancer may have aBRAF mutation.

In an embodiment, the method of treating a subject with cancer, whereinthe subject has proven refractory to other therapies but is no longer onthese therapies, includes administering to the subject an effectiveamount of a triazolone compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, incombination with a platinum-containing anticancer agent such ascisplatin, carboplatin, or oxaliplatin, wherein the cancer is breastcancer, gastric cancer, colorectal cancer, pancreatic cancer, ocularmelanoma, prostate cancer, gastrointestinal stromal tumors (GIST),advanced esophagogastric cancer, melanoma, hepatocellular cancer, solidtumor, liver cancer, head and neck cancer, small cell lung cancer,non-small cell lung cancer, bladder cancer, testicular tumor, ovariancancer, lymphoma, leukemia, multiple myeloma, or colon cancer. In anembodiment, the cancer has a KRAS mutation. In an embodiment, the cancerhas an ALK mutation. In an embodiment, the cancer has a BRAF mutation.

In an embodiment, the method of treating a subject with cancer, whereinthe subject has proven refractory to other therapies but is no longer onthese therapies, includes administering to the subject an effectiveamount of a triazolone compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, in combination with a platinum-containing anticancer agentsuch as cisplatin, carboplatin, or oxaliplatin, wherein the cancer isbreast cancer, gastric cancer, colorectal cancer, pancreatic cancer,ocular melanoma, prostate cancer, gastrointestinal stromal tumors(GIST), advanced esophagogastric cancer, melanoma, hepatocellularcancer, solid tumor, liver cancer, head and neck cancer, small cell lungcancer, non-small cell lung cancer, bladder cancer, testicular tumor,ovarian cancer, lymphoma, leukemia, multiple myeloma, or colon cancer.In an embodiment, the cancer has a KRAS mutation. In an embodiment, thecancer has an ALK mutation. In an embodiment, the cancer has a BRAFmutation.

In an further embodiment, the method includes inhibiting the growth of acancer or tumor cell comprising the steps of: (a) contacting the cellwith an effective amount of a compound of formulae (I) or (Ia) or acompound in Table (1) or Table (2), or tautomer or a pharmaceuticallyacceptable salt thereof; and (b) exposing the cell to an effectiveamount of a platinum-containing anticancer agent such as cisplatin,carboplatin, or oxaliplatin.

In an further embodiment, the method includes inhibiting the growth of acancer or tumor cell comprising the steps of: (a) contacting the cellwith an effective amount of a compound of-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof; and (b)exposing the cell to an effective amount of a platinum-containinganticancer agent such as cisplatin, carboplatin, or oxaliplatin. In anembodiment, the cancer has a KRAS mutation. In an embodiment, the cancerhas an ALK mutation. In an embodiment, the cancer has a BRAF mutation.

In another embodiment, the invention also provides a method ofinhibiting the growth of a cancer or tumor cell, comprising the stepsof: (a) contacting the cell with an effective amount of a compound of-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof; and (b)exposing the cell to an effective amount of cisplatin. In an embodiment,the cancer has a KRAS mutation. In an embodiment, the cancer has an ALKmutation. In an embodiment, the cancer has a BRAF mutation.

In another embodiment, the invention also provides a method ofinhibiting the growth of a cancer or tumor cell, comprising the stepsof: (a) contacting the cell with an effective amount of a compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or tautomer or a pharmaceutically acceptable saltthereof; and (b) exposing the cell to an effective amount of aplatinum-containing anticancer agent such as cisplatin, carboplatin, oroxaliplatin. In an embodiment, the cancer has a KRAS mutation. In anembodiment, the cancer has an ALK mutation. In an embodiment, the cancerhas a BRAF mutation.

In another embodiment, the invention also provides a method ofinhibiting the growth of a cancer or tumor cell, comprising the stepsof: (a) contacting the cell with an effective amount of a compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or tautomer or a pharmaceutically acceptable saltthereof; and (b) exposing the cell to an effective amount of cisplatin.In an embodiment, the cancer has a KRAS mutation. In an embodiment, thecancer has an ALK mutation. In an embodiment, the cancer has a BRAFmutation.

In general, the recommended daily dose range of a triazolone compoundfor the conditions described herein lie within the range of from about0.01 mg to about 1000 mg per day, given as a single once-a-day dosepreferably as divided doses throughout a day. In an embodiment, thedaily dose is administered twice daily in equally divided doses.Specifically, a daily dose range should be from about 5 mg to about 500mg per day, more specifically, between about 10 mg and about 200 mg perday. In managing the patient, the therapy should be initiated at a lowerdose, perhaps about 1 mg to about 25 mg, and increased if necessary upto about 200 mg to about 1000 mg per day as either a single dose ordivided doses, depending on the patient's global response. It may benecessary to use dosages of the active ingredient outside the rangesdisclosed herein in some cases, as will be apparent to those of ordinaryskill in the art. Furthermore, it is noted that the clinician ortreating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with individual patient response.

Different therapeutically effective amounts may be applicable fordifferent cancers, as will be readily known by those of ordinary skillin the art. Similarly, amounts sufficient to prevent, manage, treat orameliorate such cancers, but insufficient to cause, or sufficient toreduce, adverse effects associated with the triazolone compoundsdescribed herein are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a patient isadministered multiple dosages of a triazolone compound described herein,not all of the dosages need be the same. For example, the dosageadministered to the patient may be increased to improve the prophylacticor therapeutic effect of the compound or it may be decreased to reduceone or more side effects that a particular patient is experiencing.

In a specific embodiment, the dosage of the composition comprising atriazolone compound described herein administered to prevent, treat,manage, or ameliorate cancer, or one or more symptoms thereof in apatient is 150 μg/kg, preferably 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg,10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg,or 200 mg/kg or more of a patient's body weight. In another embodiment,the dosage of the composition comprising a compound described hereinadministered to prevent, treat, manage, or ameliorate cancer, or one ormore symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg,0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mgto 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg,1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5mg. The unit dose can be administered 1, 2, 3, 4 or more times daily, oronce every 2, 3, 4, 5, 6 or 7 days, or once weekly, once every twoweeks, once every three weeks or once monthly.

In certain embodiments, when the triazolone compounds described hereinare administered in combination with a platinum-containing anticanceragent, the therapies are administered less than 5 minutes apart, lessthan 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1to about 2 hours apart, at about 2 hours to about 3 hours apart, atabout 3 hours to about 4 hours apart, at about 4 hours to about 5 hoursapart, at about 5 hours to about 6 hours apart, at about 6 hours toabout 7 hours apart, at about 7 hours to about 8 hours apart, at about 8hours to about 9 hours apart, at about 9 hours to about 10 hours apart,at about 10 hours to about 11 hours apart, at about 11 hours to about 12hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hoursapart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hoursto 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hoursapart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96hours to 120 hours part. In one embodiment, two or more therapies areadministered within the same patient visit.

In certain embodiments, one or more compounds described herein and oneor more other the therapies (e.g., therapeutic agents) are cyclicallyadministered. Cycling therapy involves the administration of a firsttherapy (e.g., a first prophylactic or therapeutic agents) for a periodof time, followed by the administration of a second therapy (e.g., asecond prophylactic or therapeutic agents) for a period of time,followed by the administration of a third therapy (e.g., a thirdprophylactic or therapeutic agents) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the agents, to avoidor reduce the side effects of one of the agents, and/or to improve theefficacy of the treatment.

In certain embodiments, administration of the same compound describedherein may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, a method of preventing, treating, managing, orameliorating a proliferative disorders, such as cancer, or one or moresymptoms thereof, the methods comprising administering to a subject inneed thereof a dose of at least 150 μg/kg, preferably at least 250μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, atleast 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200mg/kg or more of one or more compounds described herein once every day,preferably, once every 2 days, once every 3 days, once every 4 days,once every 5 days, once every 6 days, once every 7 days, once every 8days, once every 10 days, once every two weeks, once every three weeks,or once a month. Alternatively, the dose can be divided into portions(typically equal portions) administered two, three, four or more times aday.

In an embodiment, the invention also provides the use of a compound offormulae (I) or (Ia), or a compound in Tables 1 or 2, or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of a subject with cancer. In an embodiment,the invention further provides the use of a compound of formulae (I) or(Ia), or a compound in Tables 1 or 2, or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for the treatment of asubject with a cancer, in combination with a platinum-containinganticancer agent such as cisplatin, carboplatin, or oxaliplatin. In anembodiment, the invention further provides the use of a compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of a subject with acancer, in combination with a platinum-containing anticancer agent suchas cisplatin, carboplatin, or oxaliplatin. In an embodiment, theinvention further provides the use of a compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, for the manufacture of a medicament for the treatment of asubject with a cancer, in combination with a platinum-containinganticancer agent such as cisplatin, carboplatin, or oxaliplatin. In anembodiment, the invention further provides the use of the compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of a subject with acancer, in combination with cisplatin. In an embodiment, the inventionfurther provides the synergistic use of the compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of a subject with acancer, in combination with cisplatin.

In an embodiment, the invention also provides a compound of formulae (I)or (Ia) or a pharmaceutically acceptable salt thereof for use intreating a subject with a cancer. In an embodiment, the invention alsoprovides a compound of formulae (I) or (Ia) or a pharmaceuticallyacceptable salt thereof for use in treating a subject with cancer incombination with a platinum-containing anticancer agent such ascisplatin, carboplatin, or oxaliplatin. In an embodiment, the inventionalso provides a compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, for use intreating a subject with cancer in combination with a platinum-containinganticancer agent such as cisplatin, carboplatin, or oxaliplatin. In anembodiment, the invention also provides a compound of5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, for use in treating a subject with cancer in combinationwith a platinum-containing anticancer agent such as cisplatin,carboplatin, or oxaliplatin. In an embodiment, the invention alsoprovides a compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, for use intreating a subject with cancer in combination with cisplatin. In anembodiment, the invention also provides a compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer, or a pharmaceutically acceptable salt thereof, forsynergistic use in treating a subject with cancer in combination withcisplatin.

Examples

In Vitro Combination Analysis of Ganetespib with Chemotherapy inColorectal Cancer Cells

A. Materials and Methods

Cell Lines

Human HCT-116 colorectal cancer cells (CRC) and MDA-MB-231 breast cancercells were purchased from the American Type Culture Collection(Manassas, Va.) and grown following ATCC recommendations, in thepresence of fetal bovine serum (10%), 2 mM L-glutamine and antibiotics(100 IU/ml penicillin and 100 μg/ml streptomycin, Sigma). Cells weremaintained at 37° C., 5% CO₂ atmosphere.

Cell Viability Assays

Cell viability was measured using the alamarBlue assay (Invitrogen). Inbrief, cells were plated in 96-well plates in triplicate at 5K cells perwell and incubated at 37° C., 5% CO₂ atmosphere for 24 hr prior to theaddition of drug or vehicle (0.3% DMSO) to the culture medium. After 72hr, 10 μl/well alamarBlue was added to the wells and incubated for anadditional 3 hr at 37° C., 5% CO₂ atmosphere. Fluorescence(56_(EX)/590_(EM) nM) was measured with a SpectraMax microplate reader(Molecular Devices) and the resulting data were used to calculate cellviability, normalized to vehicle control.

Mouse Studies

Six to seven week old, female CB17/Icr-Prkdc^(scid)/Crl (SCID) mice wereobtained from Charles River Laboratories (Wilmington, Mass., USA).Animals were housed 4-5/cage in micro-isolators, with a 12 hr/12 hrlight/dark cycle, acclimated for at least 1 week prior to use and fednormal laboratory chow ad libitum. Animals were between seven to eightweeks of age at implantation. To implant HCT-116 or MDA-MB-231 tumorcells into SCID mice, cells were harvested by trypsinization, washed inPBS and re-susupended at a concentration of 5×10(7) cells/mL in 50%non-supplemented medium and 50% Matrigel Basement Membrane Matrix (BDBiosciences; Bedford, Mass., USA). Using a 27 gauge needle and 1 ccsyringe, 5×10(6) cells in 0.1 mL of a cell suspension were injectedsubcutaneously into the flanks of SCID mice.

Tumors were then permitted to develop in vivo until the majority reached95-195 mm³ in tumor volume. Animals with oblong, very small or largetumors were discarded and only animals carrying tumors that displayedconsistent growth rates were selected for studies. Tumor volumes (V)were calculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals were randomized into treatment groups so that the average tumorvolumes of each group were similar at the start of dosing.

Ganetespib was prepared by dissolving the appropriate amounts of thecompound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonicwater bath. Stock solutions were prepared weekly, stored at −20° C. anddiluted fresh each day for dosing. A solution of 20% Cremophor RH40(polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft,Ludwigshafen, Germany) in 5% dextrose in water (Abbott Laboratories,North Chicago, Ill., USA) was also prepared by first heating 100%Cremophor RH40 at 50-60° C. until liquefied and clear, diluting 1:5 with100% D5W, reheating again until clear and then mixing well. Thissolution can be stored at room temperature for up to 3 months prior touse. To prepare DRD formulations for daily dosing, DMSO stock solutionswere diluted 1:10 with 20% Cremophor RH40. The final DRD formulation fordosing contained 10% DMSO, 18% Cremophor RH40, 3.6% dextrose, 68.4%water and the appropriate amount of test article. Animals wereintravenously (i.v.) injected with this formulation at 10 mL per kg bodyweight 1 day each week. Cisplatin was prepared fresh in saline and givenintravenously 6 hours after ganetespib injection, once per week.

B. Combination Studies with Ganetespib and Cisplatin

The half maximal inhibitory concentration (IC₅₀) for ganetespib(synthesized at Synta Pharmaceuticals) and cisplatin (purchased fromSigma) were first determined using a 1.5-fold serial dilution series ofcompound. After HCT-116 cells were exposed to drug for 72 hr, cellviability was measured and results were fit to a four parameter logisticmodel (XLFit, ID Business Solutions) shown in FIGS. 1 and 2. The IC₅₀for ganetespib was calculated at approximately 32 nM, and 5.7 μM forcisplatin.

Combinations between ganetespib and cisplatin were then performed inHCT-116 cells concurrently based on the IC₅₀ for each agent in matrixformat with 54 combination pairs for each drug. The combined drugs, aswell as each drug alone, were incubated with the cells for 3 days andthe surviving fraction of cells relative to control was determined usingthe alamarBlue assay. Representative figures are shown in FIGS. 3 and 4.The combination of ganetespib with cisplatin displayed enhancedcytotoxicity relative to single agent drugs alone. Similar results wereobserved when cells were exposed to ganetespib for just one hour, washedand then treated with cisplatin for 3 days.

Combinations between ganetespib and cisplatin were further performed inanimal models, using HCT-116 colon cancer or MDA-MB-231 breast cancertumor xenografts. Ganetespib (150 mg/kg) was given as a single bolusinjection 6 hours prior to cisplatin (2 mg/kg) administration.Representative figures are shown in FIGS. 5 and 6. In both cancerxenograft models, the combination of ganetespib with cisplatin displayedgreater antitumor activity relative to monotherapy.

In conclusion, these data support the use of ganetespib in combinationwith cisplatin in solid cancers such as gastric, bladder, colorectal,breast, ovarian and lung. See also Acquaviva et al, Mol Cancer Ther.2012, September issue.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples throughoutthe specification are illustrative only and not intended to be limitingin any way.

What is claimed is:
 1. A pharmaceutical composition comprising aplatinum-containing anti-cancer agent and an Hsp90 inhibitor accordingto the following formulae:

or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: Zis OH, SH, or NH₂; X is CR₄ or N; R₁ is —H, —OH, —SH, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, an alkoxy orcycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,—C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇,—C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇,—SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇,—OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; R₂ is —H, —OH, —SH, —NR₇H, —OR₁₅, —SR₁₅,—NHR₁₅, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH,—S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁; R₃ is —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R₇,—(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —S(O)_(p)R₇,—S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁; R₄ is —H, —OH, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanidino, a haloalkyl, aheteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,—S(O)_(p)NR₁₀R₁₁, or R₃ and R₄ taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heterocyclyl, oran optionally substituted heteroaryl; R₇ and R₈, for each occurrence,are, independently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; R₁₅, for each occurrence, is independently, a lower alkyl;p, for each occurrence, is, independently, 1 or 2; and m, for eachoccurrence, is independently, 1, 2, 3, or
 4. 2. The pharmaceuticalcomposition of claim 1, wherein the Hsp90 inhibitor is3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazoleor a tautomer or a pharmaceutically acceptable salt thereof.
 3. Thepharmaceutical composition of claim 1, wherein the Hsp90 inhibitor is5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof.
 4. The pharmaceutical composition of claim 1, wherein theplatinum-containing anticancer agent is selected from the groupconsisting of cisplatin, carboplatin, and oxaliplatin.
 5. Thepharmaceutical composition of claim 4, wherein the platinum-containinganticancer agent is cisplatin.
 6. The pharmaceutical composition ofclaim 1, wherein the Hsp90 inhibitor is3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer or a pharmaceutically acceptable salt thereof, and theplatinum-containing anticancer agent is cisplatin.
 7. The pharmaceuticalcomposition of claim 1, wherein the Hsp90 inhibitor is5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, and the platinum-containing anticancer agent is cisplatin.8. The composition of claim 1, further comprising one or more additionaltherapeutic agents selected from the group consisting of vandetanib,trastuzumab, temodar, dexamethasone, epirubicin, ifosfamide,mitoxantrone, vorinostat, interferon alpha, rituximab, prednisone,cyclophosphamide, bendamustine, adriamycin, valproate, celecoxib,thalidomide, nelarabine, methotrexate, filgrastim, gemtuzumabozogamicin, testosterone, clofarabine, cytarabine, everolimus,rituxumab, busulfan, capecitabine, pegfilgrastim, mesna, amrubicin,obatoclax, gefitinib, cyclosporine, dasatinib, temozolomide, thiotepa,plerixafor, mitotane, vincristine, doxorubicin, cixutumumab, endostar,fenofibrate, melphalan, sunitinib, rubitecan, enoxaparin, isotretinoin,tariquidar, pomalidomide, sorafenib, altretamine, idarubicin, rapamycin,zevalin, everolimus, pravastatin, carmustine, nelfinavir, streptozocin,tirapazamine, aprepitant, lenalidomide, G-CSF, procarbazine,alemtuzumab, amifostine, valspodar, lomustine, oblimersen, temsirolimus,vinblastine, figitumumab, belinostat, niacinamide, tipifarnib,estramustine, erlotinib, bevacizumab, paclitaxel, docetaxel, Abraxane®,pemetrexed, bortezomib, cetuximab, gemcitabine, 5-fluorouracil,leucovorin, and tetracycline.
 9. The composition of claim 8, wherein theone or more therapeutic agents is selected from the group consisting oferlotinib, bevacizumab, bortezomib, paclitaxel, doxorubicin, docetaxel,mitoxantrone, cytarabine, 5-fluorouracil, leucovorin, and vincristine.10. A method of treating cancer, comprising administering to the subjectan effective amount of the pharmaceutical composition of claim
 1. 11.The method of claim 10, wherein the cancer is breast cancer, gastriccancer, colorectal cancer, pancreatic cancer, ocular melanoma, prostatecancer, gastrointestinal stromal tumors (GIST), advanced esophagogastriccancer, melanoma, hepatocellular cancer, solid tumor, liver cancer, headand neck cancer, small cell lung cancer, non-small cell lung cancer,bladder cancer, testicular tumor, ovarian cancer, lymphoma, leukemia,multiple myeloma, or colon cancer.
 12. The method of claim 11, whereinthe cancer is gastric cancer, bladder cancer, pancreatic cancer,non-small cell lung cancer, ovarian cancer, or colorectal cancer.
 13. Amethod of treating colorectal cancer, ovarian cancer, pancreatic cancer,non-small cell lung cancer, or bladder cancer in a subject, comprisingadministering to the subject an effective amount of the pharmaceuticalcomposition of claim
 1. 14. The method of claim 13, wherein the methodcomprising administering a compound of3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer or a pharmaceutically acceptable salt thereof, andcisplatin.
 15. The method of claim 14, wherein cisplatin is administeredat a dose from about 20 mg/m² to about 150 mg/m².
 16. The method ofclaim 14, wherein the amount of the triazole compound is from about 2mg/m² to about 260 mg/m².
 17. The method of claim 16, wherein the amountof the triazole compound is about 75 mg/m², about 85 mg/m², about 100mg/m², about 110 mg/m², about 115 mg/m², about 120 mg/m², about 145mg/m², about 150 mg/m², about 175 mg/m², about 180 mg/m², about 200mg/m², about 215 mg/m² or about 260 mg/m².
 18. The method of claim 16,wherein the Hsp90 inhibitor is administered IV once weekly or twiceweekly.
 19. A method of inhibiting the growth of a cancer or tumor cellin a subject, the method comprising the steps of: (a) contacting thecell with an effective amount of a compound of formulae (I) or (Ia) asdefined in claim 1, and (b) exposing the cell to an effective amount ofa platinum-containing anticancer agent, wherein the platinum-containinganticancer agent is selected from the group consisting of cisplatin,carboplatin, and oxaliplatin.
 20. The method of claim 19, wherein thecompound is3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,or a tautomer or a pharmaceutically acceptable salt thereof and theplatinum-containing anticancer agent is cisplatin.
 21. The method ofclaim 19, wherein the compound is5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyldihydrogen phosphate, or a tautomer, or a pharmaceutically acceptablesalt thereof, and the platinum-containing anticancer agent is cisplatin.